AU640505B2 - Benzimidazoles - Google Patents
Benzimidazoles Download PDFInfo
- Publication number
- AU640505B2 AU640505B2 AU81227/91A AU8122791A AU640505B2 AU 640505 B2 AU640505 B2 AU 640505B2 AU 81227/91 A AU81227/91 A AU 81227/91A AU 8122791 A AU8122791 A AU 8122791A AU 640505 B2 AU640505 B2 AU 640505B2
- Authority
- AU
- Australia
- Prior art keywords
- group
- methyl
- butyl
- substituted
- biphenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- 150000001556 benzimidazoles Chemical class 0.000 title claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 87
- 239000000203 mixture Substances 0.000 claims abstract description 55
- 150000003839 salts Chemical class 0.000 claims abstract description 35
- -1 tetrahydrobenzimidazolyl Chemical group 0.000 claims description 420
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 212
- ILYSAKHOYBPSPC-UHFFFAOYSA-N 2-phenylbenzoic acid Chemical compound OC(=O)C1=CC=CC=C1C1=CC=CC=C1 ILYSAKHOYBPSPC-UHFFFAOYSA-N 0.000 claims description 93
- 239000002253 acid Substances 0.000 claims description 58
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 41
- 239000004305 biphenyl Substances 0.000 claims description 40
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 34
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 32
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 26
- 125000003277 amino group Chemical group 0.000 claims description 25
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 25
- 125000004173 1-benzimidazolyl group Chemical group [H]C1=NC2=C([H])C([H])=C([H])C([H])=C2N1* 0.000 claims description 22
- HLAYLOOJBAJIRU-UHFFFAOYSA-N 5-biphenyl-2-yl-1H-tetrazole Chemical group C1=CC=CC=C1C1=CC=CC=C1C1=NN=NN1 HLAYLOOJBAJIRU-UHFFFAOYSA-N 0.000 claims description 22
- 239000000460 chlorine Substances 0.000 claims description 21
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 20
- 125000001570 methylene group Chemical group [H]C([H])([*:1])[*:2] 0.000 claims description 20
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 17
- 125000000217 alkyl group Chemical group 0.000 claims description 15
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 15
- 125000006239 protecting group Chemical group 0.000 claims description 15
- 235000010290 biphenyl Nutrition 0.000 claims description 14
- 239000011976 maleic acid Substances 0.000 claims description 14
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 14
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 13
- 229910052801 chlorine Inorganic materials 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- 125000003831 tetrazolyl group Chemical group 0.000 claims description 13
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 12
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 claims description 12
- 239000011737 fluorine Substances 0.000 claims description 12
- 229910052731 fluorine Inorganic materials 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 claims description 12
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 11
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 11
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 10
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 10
- WVIIMZNLDWSIRH-UHFFFAOYSA-N cyclohexylcyclohexane Chemical group C1CCCCC1C1CCCCC1 WVIIMZNLDWSIRH-UHFFFAOYSA-N 0.000 claims description 10
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 10
- CGBYBGVMDAPUIH-UHFFFAOYSA-N acide dimethylmaleique Natural products OC(=O)C(C)=C(C)C(O)=O CGBYBGVMDAPUIH-UHFFFAOYSA-N 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 9
- 125000002883 imidazolyl group Chemical group 0.000 claims description 9
- 150000007524 organic acids Chemical class 0.000 claims description 9
- 206010019280 Heart failures Diseases 0.000 claims description 8
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims description 8
- 150000007522 mineralic acids Chemical class 0.000 claims description 8
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 8
- 150000001204 N-oxides Chemical class 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- 125000001624 naphthyl group Chemical group 0.000 claims description 7
- 125000001424 substituent group Chemical group 0.000 claims description 7
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 6
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 125000006598 aminocarbonylamino group Chemical group 0.000 claims description 6
- 125000006267 biphenyl group Chemical group 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 6
- 208000035475 disorder Diseases 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 6
- 238000006460 hydrolysis reaction Methods 0.000 claims description 6
- 125000004817 pentamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 claims description 6
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 claims description 6
- 125000003282 alkyl amino group Chemical group 0.000 claims description 5
- 125000004744 butyloxycarbonyl group Chemical group 0.000 claims description 5
- 238000007327 hydrogenolysis reaction Methods 0.000 claims description 5
- 125000004857 imidazopyridinyl group Chemical group N1C(=NC2=C1C=CC=N2)* 0.000 claims description 5
- 125000004458 methylaminocarbonyl group Chemical group [H]N(C(*)=O)C([H])([H])[H] 0.000 claims description 5
- 125000004888 n-propyl amino group Chemical group [H]N(*)C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 230000000269 nucleophilic effect Effects 0.000 claims description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- DUHQIGLHYXLKAE-UHFFFAOYSA-N 3,3-dimethylglutaric acid Chemical compound OC(=O)CC(C)(C)CC(O)=O DUHQIGLHYXLKAE-UHFFFAOYSA-N 0.000 claims description 4
- 125000004080 3-carboxypropanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C(O[H])=O 0.000 claims description 4
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 4
- 208000018522 Gastrointestinal disease Diseases 0.000 claims description 4
- 208000010412 Glaucoma Diseases 0.000 claims description 4
- 206010020772 Hypertension Diseases 0.000 claims description 4
- 125000003368 amide group Chemical group 0.000 claims description 4
- 229910052799 carbon Inorganic materials 0.000 claims description 4
- 125000004432 carbon atom Chemical group C* 0.000 claims description 4
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 4
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 4
- WJRBRSLFGCUECM-UHFFFAOYSA-N hydantoin Chemical group O=C1CNC(=O)N1 WJRBRSLFGCUECM-UHFFFAOYSA-N 0.000 claims description 4
- 230000000302 ischemic effect Effects 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 208000010125 myocardial infarction Diseases 0.000 claims description 4
- 208000031225 myocardial ischemia Diseases 0.000 claims description 4
- 230000002093 peripheral effect Effects 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- TVPRCLHSULCNLV-UHFFFAOYSA-N pyridazin-3-one Chemical compound O=C1C=CC=N[N]1 TVPRCLHSULCNLV-UHFFFAOYSA-N 0.000 claims description 4
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 4
- 208000026533 urinary bladder disease Diseases 0.000 claims description 4
- 125000006559 (C1-C3) alkylamino group Chemical group 0.000 claims description 3
- AAILEWXSEQLMNI-UHFFFAOYSA-N 1h-pyridazin-6-one Chemical group OC1=CC=CN=N1 AAILEWXSEQLMNI-UHFFFAOYSA-N 0.000 claims description 3
- 239000005557 antagonist Substances 0.000 claims description 3
- 125000001589 carboacyl group Chemical group 0.000 claims description 3
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 3
- 125000001841 imino group Chemical group [H]N=* 0.000 claims description 3
- 238000000926 separation method Methods 0.000 claims description 3
- 238000001149 thermolysis Methods 0.000 claims description 3
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 2
- 125000004450 alkenylene group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 150000001412 amines Chemical class 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000000440 benzylamino group Chemical group [H]N(*)C([H])([H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000000068 chlorophenyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 2
- 238000006114 decarboxylation reaction Methods 0.000 claims description 2
- CGBYBGVMDAPUIH-ARJAWSKDSA-N dimethylmaleic acid Chemical compound OC(=O)C(/C)=C(/C)C(O)=O CGBYBGVMDAPUIH-ARJAWSKDSA-N 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 125000004283 imidazolin-2-yl group Chemical group [H]N1C(*)=NC([H])([H])C1([H])[H] 0.000 claims description 2
- MTNDZQHUAFNZQY-UHFFFAOYSA-N imidazoline Chemical compound C1CN=CN1 MTNDZQHUAFNZQY-UHFFFAOYSA-N 0.000 claims description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000001301 oxygen Substances 0.000 claims description 2
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 125000003396 thiol group Chemical group [H]S* 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 2
- 150000001735 carboxylic acids Chemical class 0.000 claims 2
- 125000006698 (C1-C3) dialkylamino group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- XUSXTHMTOSFZII-UHFFFAOYSA-N 1-(aminomethyl)cyclohexan-1-ol Chemical compound NCC1(O)CCCCC1 XUSXTHMTOSFZII-UHFFFAOYSA-N 0.000 claims 1
- BTUDGPVTCYNYLK-UHFFFAOYSA-N 2,2-dimethylglutaric acid Chemical compound OC(=O)C(C)(C)CCC(O)=O BTUDGPVTCYNYLK-UHFFFAOYSA-N 0.000 claims 1
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 claims 1
- 125000005605 benzo group Chemical group 0.000 claims 1
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 claims 1
- GUQRKZPMVLRXLT-UHFFFAOYSA-N n-cyclohexylhydroxylamine Chemical compound ONC1CCCCC1 GUQRKZPMVLRXLT-UHFFFAOYSA-N 0.000 claims 1
- LMAZKPOSWVOFGY-FBAUPLQOSA-N orine Natural products CO[C@H]1C[C@H](O[C@H]2CC[C@]3(C)[C@H]4C[C@@H](OC(=O)C=Cc5ccccc5)[C@]6(C)[C@@](O)(CC[C@]6(O)[C@]4(O)CC=C3C2)[C@H](C)OC(=O)C=Cc7ccccc7)O[C@H](C)[C@H]1O LMAZKPOSWVOFGY-FBAUPLQOSA-N 0.000 claims 1
- 125000003854 p-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Cl 0.000 claims 1
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims 1
- 229940123073 Angiotensin antagonist Drugs 0.000 abstract description 4
- 239000002369 angiotensin antagonist Substances 0.000 abstract description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 287
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 270
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 129
- 238000002844 melting Methods 0.000 description 126
- 230000008018 melting Effects 0.000 description 126
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 120
- 229940073584 methylene chloride Drugs 0.000 description 90
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 81
- 239000000741 silica gel Substances 0.000 description 81
- 229910002027 silica gel Inorganic materials 0.000 description 81
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 78
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 75
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 69
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 48
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 44
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 42
- 229910021529 ammonia Inorganic materials 0.000 description 39
- 239000000243 solution Substances 0.000 description 39
- 239000002904 solvent Substances 0.000 description 34
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 31
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 30
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 28
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 26
- 239000013543 active substance Substances 0.000 description 26
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 24
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 24
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 21
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 19
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 18
- 238000001819 mass spectrum Methods 0.000 description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 15
- 229960000583 acetic acid Drugs 0.000 description 14
- 238000004440 column chromatography Methods 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- 239000012043 crude product Substances 0.000 description 13
- 239000012362 glacial acetic acid Substances 0.000 description 13
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 13
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 13
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 239000002585 base Substances 0.000 description 10
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 9
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 8
- 238000009835 boiling Methods 0.000 description 8
- 235000019359 magnesium stearate Nutrition 0.000 description 8
- 238000002390 rotary evaporation Methods 0.000 description 8
- 238000005245 sintering Methods 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- 229920002261 Corn starch Polymers 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000008120 corn starch Substances 0.000 description 7
- 150000002148 esters Chemical class 0.000 description 7
- 238000001704 evaporation Methods 0.000 description 7
- 230000008020 evaporation Effects 0.000 description 7
- 239000011541 reaction mixture Substances 0.000 description 7
- 239000001117 sulphuric acid Substances 0.000 description 7
- 235000011149 sulphuric acid Nutrition 0.000 description 7
- 239000000725 suspension Substances 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 6
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 6
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- XACWJIQLDLUFSR-UHFFFAOYSA-N pyrrolidine-1-carbonyl chloride Chemical compound ClC(=O)N1CCCC1 XACWJIQLDLUFSR-UHFFFAOYSA-N 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010288 sodium nitrite Nutrition 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- SQMCFUSVGSBKFK-UHFFFAOYSA-M sodium;5-(cyclohexen-1-yl)-1,5-dimethylpyrimidin-3-ide-2,4,6-trione Chemical compound [Na+].O=C1N(C)C(=O)[N-]C(=O)C1(C)C1=CCCCC1 SQMCFUSVGSBKFK-UHFFFAOYSA-M 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
- 229960002256 spironolactone Drugs 0.000 description 1
- 235000011150 stannous chloride Nutrition 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- YHXCWNQNVMAENQ-UHFFFAOYSA-N tert-butyl 2-[4-(bromomethyl)phenyl]benzoate Chemical compound CC(C)(C)OC(=O)C1=CC=CC=C1C1=CC=C(CBr)C=C1 YHXCWNQNVMAENQ-UHFFFAOYSA-N 0.000 description 1
- IRPIPOLLMTURMD-UHFFFAOYSA-N tert-butyl 2-[4-[(6-amino-2-butylbenzimidazol-1-yl)methyl]phenyl]benzoate Chemical compound CCCCC1=NC2=CC=C(N)C=C2N1CC(C=C1)=CC=C1C1=CC=CC=C1C(=O)OC(C)(C)C IRPIPOLLMTURMD-UHFFFAOYSA-N 0.000 description 1
- 150000003509 tertiary alcohols Chemical class 0.000 description 1
- 125000001412 tetrahydropyranyl group Chemical group 0.000 description 1
- OULAJFUGPPVRBK-UHFFFAOYSA-N tetratriacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO OULAJFUGPPVRBK-UHFFFAOYSA-N 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000011135 tin Substances 0.000 description 1
- 229910052718 tin Inorganic materials 0.000 description 1
- AXZWODMDQAVCJE-UHFFFAOYSA-L tin(II) chloride (anhydrous) Chemical compound [Cl-].[Cl-].[Sn+2] AXZWODMDQAVCJE-UHFFFAOYSA-L 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- PIILXFBHQILWPS-UHFFFAOYSA-N tributyltin Chemical compound CCCC[Sn](CCCC)CCCC PIILXFBHQILWPS-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- SBXWFLISHPUINY-UHFFFAOYSA-N triphenyltin Chemical group C1=CC=CC=C1[Sn](C=1C=CC=CC=1)C1=CC=CC=C1 SBXWFLISHPUINY-UHFFFAOYSA-N 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
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- C07—ORGANIC CHEMISTRY
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P27/06—Antiglaucoma agents or miotics
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P9/08—Vasodilators for multiple indications
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- A—HUMAN NECESSITIES
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- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
- C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
- C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
- C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
- C07D235/08—Radicals containing only hydrogen and carbon atoms
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- C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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Abstract
The invention relates to benzimidazoles of the general formula <IMAGE> in which R1 to R4 are as defined in Claim 1, mixtures of their 1-, 3-isomers, and their salts, which have valuable properties. The novel compounds are, in particular, angiotensin antagonists.
Description
SP/00/01 1 ReguLation 3.2
AUSTRALIA
PATENTS ACT 1990 640505 COMPLETE SPECIFICATION FOR A STANDARD PATENT
ORIGINAL
.4 0O ~0
S
4~ OS~ Se S S ,~a S f~9
S
a.
S
a.
S
S
.4 0 TO BE COMP~LEED BY APPLICANT Name of Applicant DR .KARL THOMAE GmbH Actual Inventor(s): Dr Berthold Narr; Dr Norbert Hauel, Dr Jacques Van Meel; Dr Wolfgang I Wienen, Dr Michael Entzeroth and Dr Uwe Ries Address for Service: CALLINAN LAWRIE, 278 High Street, Kew, 3101, Victoria, Australia hwvention Title: "BENZIMIDAZOLES" The folowtking statement is a full description of this invention, including the best method of performing it known to me:-
IA-
56779/000.562 Benzimidazoles The present invention relates to new benzimidazoles, processes for their preparation and pharmaceutical compositions containing them.
US-A-4,880,804 describes inter alia 4'-[(2-alkylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acids and 4'-[(2-alkyl-benzimidazol-l-yl)-methyl]-2-(1Hwhich are substituted in the benzimidazole ring by an alkanoylaminomethyl group and which are angiotension-II antagonists.
It has now been found that certain new benzimidazoles are even more useful angiotensin antagonists, particularly angiotensin-II antagonists.
Thus, according to one aspect the present invention provides compounds of formula I
S
;R1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl or benzoxazolyl group optionally substituted in the phenyl nucleus by a S fluorine, chlorine or bromine atom, by a C 3 -alkyl group, by a C,.
3 -alkoxy group or by a trifluoromethyl group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a SC.6-alkyl group or by a C 3 .,-cycloalkyl group; an amino 2 group substituted by a bicyclohexylcarbonyl or biphenylcarbonyl group; or a hydroxy(CS- 7 -cycloalkyl)amino carbonyl group which may additionally be substituted at the N-atom by a C 1 3 -alkyl group; an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally also substituterd by one or two C 1 3 -alkyl groups at the N-atom; a 6- or 7membered alkyleneimino or alkenyleneimino group optionally substituted by one or two C 1 3 -alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group in the above mentioned alkylene and alkenylene moieties is replaced by a carbonyl or sulphonyl group; a 3,4,5,6-tetrahydro-2(1H)-pyrimidinone group optionally substituted by a C, 3 -alkyl or phenyl(C 3 -alkyl) group; a straight-chained or branched hydroxy(C 4 -alkyi) amino carbonyl group; a maleic acid amido or maleic acid imido group optionally mono- or disubstituted by a C 1 -alkyl or by a phenyl group, in which the substituents may be identical or different; an imidazoline or imidazole group optionally substituted by a C 1 6 -alkyl group or by a C 3 7 -cycloalkyl group; an imidazolidinedione group optionally substituted by a
C
1 -alkyl group, by a phenyl(C 1 3 -alkyl) group or by a tetramethylene, pentamethylene or hexamethylene group; a
C
1 -alkylsulphonyloxy group; a benzenesulphonyloxy group optionally substituted by a C 1 -alkyl group; aC alkylamino or phenyl (C 1 -alkyl)amino group substituted *t by a C4- 6 -alkylsulphonyl group or by a phenyl(C.
3 alkyl) slphonyl group; an amino or C- 3 -alkylamino group substituted by a naphthalenesulphonyl group optionally substituted in the naphthelene ring by a di(Clalkyl)amino group or by one or two C 1 _,-alkoxy groups; a.
C 3 -alkxy group substituted in the 4- or *0 by an imidazolyl group; a Cz 5 -alkoxy group substituted the 4- or 5-position by a benzimidazolyl or tetrahydrobenzimidazolyl group; a pyridazin-3-one or z;37 p dihydro-pyridazin-3-one group optionally substituted in -3 the 2-position by an optionally phenyl-substituted C alkyl group and optionally additionally substituted at a carbon atom by 1 or 2 Cl- 3 -alkyl groups; a pyrrolidino, piperidino or hexamethyleneimino group substituted by two Cl- 3 -alkyl groups; a 7-nitrobenzofurazan-4-ylamino (C 2 3 -alkanoyl) amino group; a heptamethyleneixnino, 1H,3H-quinazolin-2,4-dion-3-yl, pentamethylene--oxazolin- 2-yl, benzofuran-carbonylamino or 7-nitro-benzofurazan- 4-yl-amino group, and where R. represents a carboxy group and R, represents an n-butyl group, R 1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexylinethylcarbonyl, 2-tert butoxycarbonyl-cyclohexylmethylcarbonyl, 2-carboxy-3,4,5, 6-tetrahydrobenzoyl, N-methylphenylaminocarbonyl or 3-cyclohexyipropyl group; a methylamino group substituted by a propylsulphonyl, phenylsulphonyl, methylphenylsulphonyl or chiorophenylsulphonyl group; an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl group7 an npropylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group: an isopropylamino group se substituted by a benzoyl or chlorophenylsulphonyl. group; an N-acetyl-cyclohexylmethylamino, 3,4,5, 6-tetrahydrophthalimido, hexahydrohomophthalimido, 5 N-methanesulphonyl-2-phenylethylai~tino, N-chlorophenylsulphonyl-benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and
R
3 represents a carboxy group and R 2 represents an 4 methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R 1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methyl-aminocarbonyl or cyclohexylaminocarbonyl group, and R 1 in the 6-position may also represent a 3,3dimethyl-glutaric acid imido or 4,4-tetramethyleneglutaric acid imido group, and a*.
0 where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R 1 in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R 3 represents a tert.butoxycarbonyl group and R 2 represents an n-butyl group, R i in the 6-position may also represent a 2-carboxycyclohexylmethylcarbonylamino or pyrrlidinocarbonylamino group;
R
2 represents a hydrogen atom or a straight-chained or branched C 1 s-alkyl group in which a methylene group may optionally be replaced by a sulphur atom;
S*
R
3 represents a carboxy, cyano, 1H-tetrazolyl or 1triphenylmethyl-tetrazolyl group or a (C 1 4 -alkoxy)carbonyl group; and
R
4 represents a hydrogen, fluorine, chlorine or bromine atom); and isomers, especially the l-,3-isomer mixtures, and salts thereof, in particular, for pharmaceutical use the physiologically acceptable salts thereof with organic or inorganic acids or bases.
The following are examples of the definitions of the groups R, and R 2 as mentioned hereinbefore: R, may represent a benzimidazol-2-yl, I-methylbenzimidazol-2-yl, i-ethyl-benzimidazol-2-yl, 1-npropyl-benzimidazol-2-yl, 1-isopropyl-benzimidazol-2-yl, 1-n-butyl-benzimidazol-2-yl, 1-n-penty,'L-benzimidazol-2yi, l-n-hexyl-benzimidazol-2-yl, 1-cycb')propylbenzimidazol-2-yl, 1-cyclopentyl-benzi,.nidazo-2-y,, 1cyclohexyl-benzinidazol-2-yl, 1-cycloheptylbenzimidazol-2-yl, 1, 5-dimethyl-benzimidazol-2-yl, 1,6dimethyl-benzimidazol-2-y1, :benzimidazol-2-yl, 1-methyl-5-fluoro--Lenzimidazol-2-yl, 1-methyl-5-chloro-benzinidazol-2-yi, 1-methy1l-S-bromobenzimidazol-2-yl, 1-methyl-5-4l:rifluoromethylbenzimidazol-2-yl, tetrahydro-benziinidazol-2-yl, 1- 0 *0 0methyl-tetrahydro-benzinidazol-2-yl, 1-ethyl-tetrahydrobenzimidazol-2-yl, 1-n-propyl-tetrahydro-benzimidazol-2y1, 1-isopropyl-tetrahydro-benzinidazol-2-yl, 1-n-butyltetrahydro-benzimidazol-2-yl, 1-n-pentyl-tetrahydrobenzimidazol-2-yl, 1-n-hexyl-tetrahydro-benzimidazol-2- 0, yl, 1-cyclopropyl-tetrahydro-benzimidazol-2-yl, 1- 00 cyclopentyl-tetrahydro-benzimidazol-2-yl, 1-cyclohexyl- :00 0..*tetrahydro-benzimidazol-2-yl, 1-cycloheptyl-tetrahydrobenzimidazol-2-yl, benzoxazol-2-yl, 2-yl, 5-methoxy-benzoxazol-2-yl, us benzoxazol-2-yl, 5-fluoro-benzoxazol-2-yl, 0 0 0 benzoxazol-2-yl, 5-bromo-benzoxazol-2-yl, 4-biphenylylcarbonylamino, 4-cyclohexylcarbonylanino, N-methyl-4biphenylylcarbonylamino, N-ethyl-4 -cyclohexylcarbonylamino, N-n-propyl-4-biphenylylcarbonylamino, Nisopropyl-4-cyclohexylcarbonyaritino, 2-hydroxycyclopentylamino, 2-hydroxy-cyclohexylamino, 2-hydroxycycl1oheptylamino, 3-hydroxy-cyc3.opentylamino, 3-hydroxycyclohexylamino, 3-hydroxy-cycloheptylamin 4-hydroxycyclohexylamino, 4-hydroxy-cycloheptylaIaino, N-methyl-2hydroxy-cyclopentylamino, N-ethyl-2-hydroxycyclohexylamino, N-isopropyl-2-hydroxy-oycloheptylamino, -6 N-methyl-3-hydroxy-cyclopentylamino, N-ethyl-3-hydroxycyclohexylamino, N-n-propyl-3-hydroxy-cycloheptylamino, N-methyl-4-hydroxy-cyclohexylamino, N-ethyl-4-hydroxycycloheptylamino, 4-biphenylylaxninocarbonylamino, 4bicyclohexylaninocarbonylamnino, N- (4-biphenylylaminocarbonyl) -methylamino, N- (4-bicyclohexylaIminocarbonyl) methylamino, N- (methyl-4-biphenylylaminocarbonyl) methylamino, N- (nethyl-4-bicyclohexylaminocarbonyl) inethylamino, N- (4-biphenylylaniinocarbonyl) -ethylamino, N- (4-bicyclohexylaminocarbonyl) -isopropylaino, NIl (ethyl--4-biphenylylaminocarbrnyl) -methylamino, N- :(imethy-4-bicyclohexylaminocarbonyl) -ethyla-mino, pyrrolidin-2-on-1-yi., piper-idin-2-on-1-yl, hexaiethyleneimino-2-on-1--yl, propanesultarn-1'-yl, butanesultam-1-yl, pentanesultam-1-yl, 3,4,5,6tetrahydro-2 (1H) -pyrimidon-1-y1, 3-methyl-3, 4,5,6Etetrahydro-2 (iN)-pyrimidon-lyl, 3-ethyl-3 ,4,5,6tetrahydro-2 (1H) -pyrimidon-1-yi, 3-n-propyl-3, 4,5,6tetrahydro-2 (1H) -pyrimidon-1-yl, 3-isopropyi-3, 4,5,6tetrahydro-2 (1H) -pyriimidon-2.-yl, 3-berxzyl-3 ,4,5,6tetrahydro-2 (iH)-pyrimidon-i-yl, 3- (2-phenylethyl) 3,4,5,6-tetrahydro-2 -pyrimidon-i-yl, 3-(3- 0 Us* pheny2.propyl) 6-tetrahydro-2 (iN)-pyrimidon-i-yi, 4 -hydroxybutylamino, 5-hydroxypentyiamino, 6-hydroxyhexylamino, maleic acid imido, 2-mtethyl-maleic acid so 0 0, imido, 2-phenyl-maleic acid imido, 2,3-dinethy--Tnaleic acid inido, 2,3-diphenyl-maleic acid imido, 2-methylmaleic acid amido, 3-methyl-rialeic acid amido, 2,3dimethyl-maleic acid amido, 2-phenyl-maleic ac~id amido, 3-phenyl-inaleic acid avido, 2,3-diphenyl--maleic acid ainido, 3-methyl-2-phenyi-maleic acid amido, 2-methyi-3phenyi-maleic acid amido, inidazoiin-2-yi, i-methylimidazoiin-2-yi, i-ethi-imidazoiin-2-y., 1-propylimidazolin-2-yl, imidazoiidin-2, 4-dion-3-yi, imidazoiidin-2 ,4-dion-3-yi, 5-ethyi-imidazoiidin-2 ,4dion-3-ylo 5-n-propyi-imidazolidin-2, 4-dion-3-yl, berizyi-imidazoiidin-2, 4-dion-3-yi, 5- (2-phenylethyl) -7 imidazolidin-2 ,4-dion-3-yl, 5- (3-phenyipropyl) imidazolidii-2 ,4-dion-3-yl, 5, imidazolidin-2,4-dion-3-yl, 5, ixnidazolidin-2, 4-dion-3-yl, 5, imidazolicl 4 n-2 ,4-dion-3-yl, 5, 2,4-dion-3-yl, 5,5-diethyl-imidazolidin-2,4-dion-3-yl, methanesuiphonyloxy, ethanesuiphonyloxy, propanesuiphonyloxy, butanesuiphonyloxy, pentanesuiphonyloxy, hexanemilphonyloxy, benzenesulphonyloxy, p-toluenesulphonyloxy, N-n-butanesulphonyl-methyanino, N-n-pentanesulphonyl-methylanino, N-n-hexanesulphonm 1- Go methylamino, N-phenylmethanesulphonyl-miethylamino, N- (2- .0.0phenylethanesuiphonyl) -iethylainino, N-(3-phenylpropane- 4 suiphonyl) -iethylamino, N-n-butanesulphonyl-ethylamino, N-n-pentanesu7.phonyl-isopropylaiino, N-nhexanesuiphonyl-ethylamino, N-phenylmethanesulphonylethylamino, N- (2-phenylethanesulphonyl) -n-propylamino, N- (3-phenylpropanesulphonyl) -ethylamino, naphthalen-lsuiphonylamino, naphthalen-2-sulphonylamino, Goose dimethylamino-naphtlhalen-3.-sulphonylamino, NoP. (naphthalen-1-sulphonyl) -iethylamino, N- (naphthalen-2suiphonyl) -ethylamino, (5-dimnethylaminio-naphthalen-1suiphony.) -methylanino, N- suiphonyl) -methylamino, N- 6-dimethoxy-naphthalen-2suiphonyl) -ethylaiftino, 3- (i-idazoi-1-yl) -propoxy, 4- :00 (imidazol-1-yl) -butoxy, 5-(iinidazol-1-yl) -pentoxy, 2- (benzimidazol'-1-yi) -ethoxy, 3-(benzimidazol-1-yl) propoxy 4-(benzimidazol-1-yl)-butoxy, 1-yl) -pentoxy, 2- (tetrahydrobenziinidazol-1-yl) -ethoxy, 3- (tetrahydrobenzixnidazol-1-yl) -propoxy, 4- (tetrahydrobenzimidazol-1-yl) -butoxy, 5- (tetrahydrobenzimidazol-lyl) -pentoxy, 4, 5-dihydro-211-pyridazin-3-on-6-yl, 2mnthyl-4,5-dihydro-2H-pyridazin-3-on-6-y1, 2-ethyl-4 dih~wdro-2H-pyz'idazin-3-on-6-yl, 2-n-propyl-4, 5-dii1ho--,- 2H-pyridazin-3-on-6-yl, 2-isopropyl-4 ,5-dihydro-2Hpyridazii-3-on-6-y., 2-benzyl-4 ,5-dihydro-2H-pyridaz in- 3-on-6-yl, 2- (2-phenylethyl) 5-dihydro-2H-pyridazin-3on-6-yl, 2- (3-phenyipropyl) 5-dihydro-2H-pyridazin-3on-6--yl, 4-methyl-4, 5-dihydro-2H-pyridazin-3-on-6-yl, methy).-4, 5-dihydro-2H-pyridaziri-3-on-6-yl, 4, 4-dimethyl- 4, 5-dihydro-211-pyridazin-3-on-6-yl, 5, 5-di-nethyl-4 dihydro-2H-pyridazin-3-on-6-yl, 4, 5-dimethyl-4, dihydro-2H-pyridazin-3-on-6-yl, 2, 4-dimethyl-4, dihydro-2H-pyridazin-3-on-6-y., 2, 5-dimethyl-4, dihyc1~ro-2H,,-pyridazin-3-on-6-yl, 2,4, 5-trimethyl-4, dihydro-2H--pyridazin-3-on-6-yl, 2,4, 4-trimethyl-4 dihydro-2H-pyridazin-3-on-6-yl, 2,5, 5-trimethyl dihydro-2H-pyridazin-3-on-6-yl, 2H-pyridazin-3-on,-6-yl, 2-methyl-2H-pyridazin-3-ol-6-yl, 2-ethyl-2H-pyridazin-3on-6-yl, 2-n-propyl-2H-pyridazin-3-on-6-yl, 2-isopropyl- 2H-pyridazin-3-on-6-yl, 2-benzyli-2H-pyridazin-3-on-6-yl, 2- (2-pheriylethyl) -2H-pyridazin-3-on-6-yl, 2- (3phenyipropyl) -2H-pyridazin-3-on-6-yl, 4-methyl-2Hpyridazin-3-on-6-yl, 5-4liethyl-2H-pyridazin-3-on-6-yl, 4, 5-dimethyl-2H-pyridazin-3-on-6-yl, 2, 4-dimethyl-2Hpyridazin-3-on-6-yl, 2, 5-dimethyl-2H-pyridazin-3-ol-6yl, 2,4, 5-t-imethy-2H-pyridazin-3-on-6-y1, 3,3dimethyl-pyrrolidino, 3, 4-dinethyl-pyrrolidino, 3,3dimethyl-piperidino, 3 ,4-dimethylpi.peridino, 4,4dimethyl-piperidino, 3, 3-dime.thyl-hexainethyleneimino, 3, 4-dimnethyl-hexaxnethyleneimi4no, 4, 4-dimethyliexamethyleneimino, 3, phenylsuiphonylamino, cyclohexylinethylaminocarbonylamino, 2-methylamino-benzoylaino, 2-carboxy-cyclohexylmethylcarbonylamino, 2-tert butoxycarbonylcyclohz xylmothylcarbonylamino, 2-carboxy-3, 4,5,6tetrahydrobenzoylamino, 3-cyclohexylprepylamino, N propyisulphonyl-methylaraino, N-phenylsulphonylmethylamino, N- (4-iethy:lphenylsulphonyl) -methylam-ino, N- (4-chlorophcnylsulphonyl) -methylamino, N-phenylsulphonyl-n-pentylamino, N- (4-methoxyphenylsulphonyl) -npentylami no, N- (4 -methylphenyl sulphonyl) -n-propyl.amino, (4-methoxypheiiylsulphinyl) -n-propylamino, N-benzoylisopropylamino, N- (4-chlorophenylsulphonyl) -isopropyl- -9amino, N-acetyl-cyclohexylmethylamino, 3,4,5,6tetrahydrophthalimido, hexahydrophthal imido, N-methanesulphonyl-2-phenylethylamino, N-chlorophenylsulphonylbenzylamino, piperidino, 4 -methyl-piperidino, hexamethy) eneimino, 3-carboxy-propionyl, 3-carboxy-2methyl-propionyl, pyrrolidinocarbonylamino, Nmethylaminocarbonyl-n-pentylamino, N-cyclohexylaminocarbonyl-n-pentylamino, 3, 3-dimethyl-glutaric acid imido, 4,4-tetramethylene-glutaric acid imido, 2carboxy-cyclohexylmethylcarbonylamino, 1-n-butylimidazolin-2-yl, 1-n-pentyl-imidazolin-2-yl, l-n-hexylimdzln2-l -ylprpliiaoln2y,1 S. cyclobutyl-imidazolin-2-yl, l-cyclohexyl-imidazolin-2yl, l-cycloheptyl-imidazolin-2-yl, imidazol-2-yl, 1emBOSSmethyl-imidazol-2-yl, i-ethyl-imidazol-2-yl, 1-propyl- 0* imidazol-2-yl, l-n-butyl-imidazol-2-yl, l-n-pentyl-1 imidazol-2-yl, 1-n-hexyl-imidazol-2-yl, 3-cyclopropylimidazol-2-yl, 1-cyclobutyl-imidazol-2-yl, 1-cyclohexylimidazol-2-yl or l-cycloheptyl-imida~il-2-yl group; and 555 R 2 may represent a hydrogen atom, a methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl, tert.-butyl, npentyl, 1-methyipropyl, 1-methylbutyl, 2-methylbutyl, 3methylbutyl, 1-ethyipropyl, 1 ,l-diethylethyl, methylmercaptomethyl, 2 -methylmercapto-ethyl, 3methylmercaptopropyl or 4 -methylmercaptobutyl group.
Preferred compounds according to the invention include those of formula I wherein
R
1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally r-abstituted in the phenyl nucleus by a fluorine, chlorine or bromine atom or by a me~thyl, methoxy or trifluoromethyl group, and in which the NHgroup of the above-mentioned imidazole rings may additionally be substituted by a C 1 6 -alkyl group or by a 10
C
3 6 -cycloalk'l group; a benzoxazol-2-yl group optionally substituted by a methyl group; an amino group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl or benzofuryl-2-carbonyl group; an aminocarbonylamino group substituted in the 3-position by a bicyclohexyl or biphenyl group; a 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two methyl groups or by a tetramethylene or pentamethylene :oup wherein a methylene group is replaced by a carbonyl or sulphonyl group; a 3,4,5,6tetrahydro-2(1H)-pyrimidinone group optionally substituted by a methyl or benzyl group; a hydroxy(C 4 alkyl)aminocarbonyl group, a maleic acid amido or maleic acid imido group optionally substituted by one or two substituents which may be the same or different selected from methyl and phenyl groups; an imidazolin-2-yl or imidazol-2-yl group substituted in the 1-position by a
C
1 -alkyl group or by a C 3 -cycloalkyl group; an imidazolidinedione group optionally substituted by a methyl, benzyl, tetramethylene or pentamethylene group; a methylamino or benzylamino group substituted by a butanesulphonyl group or by a phenylmethanesulphonyl group; an amino or methylamino group substituted by a naphthalenesulphonyl roup in which the naphthalene ring may be substituted by a dimethllamino group or by 2 methoxy groups, a pyridazin-3-one or dihydro-pyridazin- 3-one group optionally substituted by a methyl or benzyl group; a pyrrolidino, piperidino or hexamethyleneimino group substituted by two methyl groups; a heptamethyleneimino, 1H,3H-quinazolin-2,4-dion-3-yl, hydroxycyclohexylamino-carbonyl, oxazolin-2-yl, 7-nitro-benzofurazan-4-yl-amino or 7nitro-benzofurazan-4-yl-aminopropionylamino group, and where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent an amino group substituted by a phenylsulphonyl, 11 cyclohexylmethylaminocarbonyl, 2-carboxycyclohexymethylcarbonyl, 2-tert. -butoxycarbonyl-cyclohexylmethylcarbonyl, 2--carboxy-3 6-tetrahydrobenzoyl, Nmethyl-phenylaininocarbonyl or 3-cyclohexylpropyl group; a methylamino group substituted by a propylsulphonyl, phenylsuiphonyl, 4-methyiphenylsuiphonyl or 4chlorophenylsulphonyl group; an n-pentylainino group substituted by a phenylsuiphonyl or 4' ,itho),yphenylsulphonyl group; an n-propylamino group substituted by a 4-inethyiphenylsuiphonyl or 4-methoxyphenylsulphonyl group; an isopropylamino group substituted by a benzoyl or 4-chiorophenylsulphonyl group, an N-acetylcyclohexylnethyJ,amino, 3,4,5, 6-tetrahydrophthalimido, hexahydrohomophthal imido, N-methanesulphonyl -2phenylethylamino, N-(4-chlorophenylsulphonyl) benzylamino, piperidino, 4-methyl-piperidino or hexamethylenejinino group, and where R. represents a carboxy group and R. represents an n-butyl'group, R, in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrolidin-l-y3., 3-carboxy-propionyl or 3-carboxy-2methyl-propionyl group, and where R 3 represents a carboxy group and R represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto
R
1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylaminocarbonyl or cyclohexylaminocarbonyl group and
R
1 in the 6-position may also represent a 3,3-dimethylglutaric acid imido or 4,4-tetramethylene-glutaric acid imido group, and 12 where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R i in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R 3 represents a tert.butoxycarbonyl group and R 2 represents an n-butyl group, R i in the 6-positic.n may also represent a 2-carboxy-cyclohexy.methylcarbonylamino or pyrrolidinocarbonylamino group;
R
2 represents a hydrogen atom or a straight-chained or branched C 1 4 -alkyl group in which a methylene group may be replaced by a sulphur atom;
R
3 represents a carboxy, cyano, 1H-tetrazolyl or 1triphenylmethyl-tetrazoiyl group or a 4 -alkoxy)carbonyl group; and
R
4 represents a hydrogen, fluorine, chlorine or bromine *4 atom; and isomers and salts thereof, especially the 3isomer mixtures thereof, and particularly the physiologically acceptable salts thereof with organic or inorganic acids or bases.
Particularly preferred compounds according to the S: invention include those of formula I wherein
R
i in the 6-position represents a l-methylbenzimidazol-2yl, 3,4,5,6-tetrahydro-phthalimino, 2,3-diphenyl-maleic acid imido, 2,3-dimethyl-maleic acid imido, N-phenylmethanesulphonyl-methylamino, 2-oxo-pyrrolidin-l-yl, 2oxo-piperidin-l-yl, 2-oxo-hexamethyleneimino, 2-oxo-3,4tetramethylene-pyrrolidin-l-yl, 3,3-dimethylglutarimido, N-methylaminocarbonyl-n-pentylamino, propanesultam-l-yl or butanesultam-l-yl group; 13-
R
2 represents a methyl, ethyl, n-propyl or n-butyl group;
R
3 represents a carboxy or 1H-tetrazolyl group; and
R
4 represents a hydrogen atom; and the isomers and salts, especially the isomer mixtures thereof and particularly the physiologically acceptable addition salts thereof with organic or inorganic acids or bases.
Although the present invention relates to new compounds of formula I, the corresponding cyano, tert.butoxycarbonyl and triphenylmethyl compounds, in particular, represent valuable intermediates which can readily be converted to one of the pharmacologically active compounds.
According to a further aspect the invention also provides a process for the preparation of compounds of the invention, said process comprising at least one of •the following steps: a) cyclising a compound of formula II (wherein
R
I is as hereinbefore defined; one of the groups X 1 or Y 1 represents a group of formula 1 r 14 3 4
N
R
and the other group X 1 or Y 1 represents a group of formula Z1 Z2 NH- C -R 2 9*
R
2
R
3 and R4 are as hereinbefore defined;
R
5 represents a hydrogen atom or an R 2 CO group; Z and Z 2 which may be the same or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl
C
1 alkyl) groups, or Z and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C 1 3 -alkyl group, or a C 2 3 -alkylenedioxy or C 2 3 alkylenedithio group, with the proviso that one of the groups X 1 or Y must represent a group of formula 4
-N
COR
2 or
Z
i
Z
2 NH or an N-oxide thereof2 NH C R 2 or an N-oxide thereof 15 and subsequently if necessary reducing the cyclized Noxide product; b) reacting a benzimidazole of formula III 1 1 1 (wherein
R
1 and R 2 are as hereinbefore defined) with a biphenyl compound of formula IV 0e
S
0@ 5 9 05 p
S
(IV)
(wherein
R
3 and R 4 are as hereinbefore defined; and
Z
3 represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a substituted sulphonyloxy group, e.g. a methanesulphonyloxy, phenylsulphonyloxy or ptoluenesulphonyloxy group); c) (to prepare a compound of formula I wherein R 3 represents a carboxy group) converting a compound of formula V SN
(V)
.16 16 (wherein
R
2 and R 4 are as hereinbefore defined; R is a group R 1 as hereinbefore defined or a alkoxy)carbonyl)propionyl or 3-((C 1 3 -alkoxy)carbonyl)-2methylpropionyl group; and
R
3 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; d) (to prepare -a compound of formula I wherein R 3 represents a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula VI R R 2) R4 S*(wherein R1, R 2 and R 4 are as hereinbefore defined; and R 3"11 represents a 1H-tetrazolyl group protected in the 1or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R 3 S* represents a 1H-tetrazolyl group) reacting a compound of formula VII
R
1 (v I) -17- (where in
R
1 R 2 and R4are as hereinbefore defined) with hydrazoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R 1 represents a pentamethylene-oxazolin-2-yl group) reacting a compound of formula VIII HOO-C R? (Vill) 0 *9 O es* (wherein *R R, R 3 and R 4 are as hereinbef ore def ined) with 1- 02 a 0 saminomethyl-cyclohexanol in the presence of an acidactivating agent; g) (to prepare a comlpound of formula I wherein R represents a 2-oxlo-3 ,4-tetramethylene-pyrrolidin-1-yl group) hydrogenating a compound of formula IX 000 0 h)(opeaecmondso ml I whereinIx) reprsent anamin grop sbstiutedbyN :iylhxycroy or*peycronlgop hc 18 may additionally be substituted at the N-atom by a C1-3 alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally additionally substituted by one or two C .alkyl groups at the N-atom, a maleic acid amido or maleic acid imido group optionally mono- or disubstituted by substituents selected from Cl--alkyl and phenyl groups, a (C 1 3 alkyl) amino or phenyl(Cl--alkyl) amino group substituted by a C 4 6 -alkylsulphonyl group or by a phenyl (C1-3alkyl)sulphony group, an amino or C 1 3 -alkylamino group substituted by a naphthalenesulphonyl group and optionally substituted in the naphthalene ring by a *c di(C 1 -alkyl)amino group or by one or two C 1 3 -alkoxy groups, a 7-nitro-benzofurazan-4-yl-amino
(C
2 -3- SO_ alkanoyl) amino group, a benzofurancarbonyl-amino or 7nitro-benzofurazan-4-yl-amino group, and S where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 6-position mhy also represent an amino group substituted by a phenylsulphonyl, cyclohexylmethylamino-carbonyl, 2carboxycyciohexylmethylcarbonyl, 2 -tert. -butoxycarbonyl- .00.
cyclohexylmethylcarbonyl, 2-carboxy-3 ,4,5,6tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3a..cyclohexylpropyl group, a methylamino group substituted by a propylsulphonyl, phenylsiAlphonyl, methylphenylsulphonyl or chlorophenylsulphonyl group, an 0O n-pentylamino group substituted by a phenylsuiphonyl or methoxyphenyl ;;ulphonyl group, an n-propylamino group substituted by a methylphenylsulphonyl or methoxyphenylsulphonyl group, an isopropylamino group substituted by a benzoyl or chlorophenylsulphonyl group, an N-acetylcyclohexylmethylamino, 3,4,5,6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2phenylethylamino or N-chlorophenylsulphonyl-benzylamino group, and 19 where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylenepyrrolidin-l-yl group, and where R 3 represents a carboxy group and R 2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R 1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylamino-carbonyl or cyclohexylaminocarbonyl group and R 1 in the 6-position may also represent a 3,3dimethyl-glutaric acid imido or 4,4-tetramethylene- S glutaric acid imido group, and where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R 1 in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and a. 6 where R 3 represents a tert.-butoxyearbonyl group and R 2 represents an n-butyl group, R I in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group) reacting a compound of formula X
S
H i
N
N _R2 (x) SR3 R 4 (wherein
R
2
R
3 and R 4 are as hereinbefore defined; and
R
6 represents a hydrogen atom, an n-pentyl, cyclohexylmethyl, Cl- 3 -alkyl or phenyl(C 3 -alkyl) group) with a compound of formula XI
Z
4
R
7
(XI)
(where in
Z
4 represents a nucleophilic leaving group; W represents a -CO- or -So 2 group; and
R
7 represents a 2-hydroxycarbonyl-ethenyl group wherein the ethenyl moiety is mono- or disubstituted by ',.substituents selected from C 13 -alkyl and phenyl groups, 9. 9 hey a 3 6 -alkyl group, a-hnlC 3 -alkyl) group, a :naphthalene group optionally substituted by a di(Cl- 3 alkyl)amino group or by one or two C 1 alkoxy groups, a 91-3 methyl, phenyl, methylphenyl, methoxyphenyl, chlorophenyl, biphenyl, bicyclohexyl, 2-carboxycyclohexylmethyl, 2-carboxy-3, 4,5, 6-tetrahydrophenyl, 3carboxy-l, 1-dimethyl-propyl, 3-carboxy-2, 2tetramethylenepropyl, 7-nitro-benzofurazan-4-ylaminomethyl. or 7-nitro-benzofurazan-4-yl-amuinoethy1 :group, and *where W represents a -CO- group, R 7 may also represent an
R.RR
9 group wherein
R
8 represents a hydrogen atom or a C.
3 -alkyl group, 940 8
R
9 represents a methyl, cyclohexyl, cyclo hexylmethyl, phenyl, biphenyl. or bicyclohexyl.
group, or Rand R9, together with the nitrogen atom between them represent a pyrrolidiro group, or
Z
4 together with R 9 represents another carbon- 21 nitrogen bond, and
R
7 together with W may also represent a 7-nitrobenzofurzizan-4-yl -amino group) or a reactive derivative of a carboxylic acid of formula XI; i) (to prepare compounds of formula I wherein R 1 reb~resents a tetrahydrobenzimidazolyl or imidazopyridinyl group, or a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine cr bromine atom, by a Cl- 3 -alkyl group, by a Cl, 3 -alkoxy group or by a trifluoromethyl ,..group, and in which the NH-group of the above-mentioned imidazole rings may additionally be substituted by a :Cl- 6 -alky'L group or by a C 7cycloalkyl group, a hydroxy(C 5 cycloalkyl)aminoca-bonyl group, which may *additionally be substitut6ed at the N-atom by a C 1 3 -alkyl group, or a straight-chained or branched hydroxy(C 4 6 alkyl)aminocarbonyl group) reacting a compound of formula XII N R :6 0 9 9 9(wherein R 2
R
3 an R are as h'3reiabeiore defined) or a reactive derivative thereof, for example an acid halide, ester, amide, anhydride or nitrile, with an amine of fcrmula
XIII
Ro N- H
(XIII)
R
11 22 (wherein
R
1 0 represents a hydrogen atom, a cycloalkyl group or a
C
1 ,.-alkyl group; and R11 represents a C 4 .6-hydroxyalkyl group, a Cs-7-hydroxycycloalkyl group or a 2-aminophenyl group which may be substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C 1 3 -alkyl group, by a C.
3 alkoxy group or by a trifluoromethyl group, a 2aminocyclohexyl or 2-aminopyridyl group) optionally with simultaneous decarboxylation; j) (to prepare compounds of formula I wherein R 1 represents a dihydro-pyridazin-3-one or a pyridazin-3one group which ray be substituted in the 2-position by an optionally phenyl-substituted C 13 -alkyl group or at a carbon atom by one or two C 1 3 -alkyl groups) reacting a carboxylic acid of formula XIV HOOC-A-C (XI V) R
R
(wherein RI, R 2
R
3 and R4 are as hereinbefore defined; and A represents an ethylene or ethenylene group optionally •substituted by one or two C 1 3 -alkyl groups) or a reactive acid derivative thereof, for example an ester, amide or halide thereof, with a hydrazine of formula XV
H
2 N NHR, 1
(XV)
(wherein
R
12 represents a hydrogen atom or an optionally phenylsubstituted C 1 3 -alkyl group); 23 k) resolving a isomer mixture of a compound of formula I by isomer separation into the 1- and 3isomers thereof; 1) converting a compound of formula I into an addition salt thereof, more particularly, for pharmaceutical use into a physiologically acceptable salt thereof with an organic or inorganic acid or base or converting a salt of a compound of formula I into the free compound; and m) carrying out a reaction according to any one of steps to above in which one or more groups are protected by a protecting group and subsequently removing any protecting group used.
In the reactions described above, any reactive groups present such as hydr'xy, amino or alkylamino groups may optionally be protected during the reaction by conventional protecting groups which are split off again after the reaction.
Examples of suitable protecting groups for a hydroxy group are trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert.-butyl, benzyl or tetrahydropyranyl groups and suitable protecting groups for an amino, alkylamino or imino group include acetyl, benzoyl, ethoxycarbonyl and benzyl groups.
The optional subsequent cleaving of a protecting group is preferably carried out by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassium hydroxide, conveniently at temperatures between 0 and 100°C, preferably at the boiling temperature of the reaction mixture. However, a 24 benzyl group is preferably removed by hydrogenolysis, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid, conveniently at temperatures between 0 and 50°C, but preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to bar.
The cyclisation of step may conveniently be carried out in a solvent or mixture of solvents such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide, tetraline or in an excess of the acylating agent used to prepare the compound of formula II, e.g. in the corresponding nitrile, anhydride, acid halide, ester or amide. The reaction is conveniently effected at temperatures between 0 and 250°C, preferably at the boiling temperature of the reaction mixture, optionally in the presence of a condensing agent such as phosphorusoxychloride, thionylchloride, sulphurylchloride, sulphuric acid, p- ***toluenesulphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid or acetic anhydride, or optionally in the presence of a 0 a* base such as potassium ethoxide or potassium tert.- *S butoxide. However, cyclisation may also be carried out without a solvent and/or condensing agent.
It is particularly advantageous to carry out the reaction of step by preparing a compound of formula II in the reaction mixture by reducing a corresponding o-nitro-amino compound, optionally in the presence of a carboxylic acid of general formula R 2 COOH, or by acylating a corresponding o-diamino compound. When the
O
25 reduction of the nitro group is broken off at the hydroxylamine stage, the N-oxide of a compound of formula I is obtained in the subsequent cyclisation.
The resulting N-oxide is then converted by reduction into a corresponding compound of formula I. The subsequent reduction of the N-oxide of formula I obtained is preferably carried out in a solvent such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethylformamide, with hydrogen in the presence of a hydrogenation catalyst such as Raney nickel, platinum or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid such as acetic, hydrochloric or sulphuric acid, with salts such as iron(II)sulphate, tin(II)chloride or sodium a: dithionite, or with hydrazine in the presence of Raney nickel at temperatures between 0 and 50 0 C, preferably at
S
ambient temperature.
The reaction of step may conveniently be carried out in a solvent or mixture of solvents such as methylene chloride, diethylether, tetrahydrofuran, dioxane, dimethyl-sulphoxide, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium tert.-butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, conveniently at temperatures between 0 and 100°C, preferably at temperatures between ambient temperature and 50"C. A mixture of the 1- and 3isomers i.s preferably obtained.
In step functional derivatives of the carboxy group such as optionally substituted amides, esters, thiolesters, orthoesters, iminoethers, amidines and anhydrides, and nitrile and tetrazolyl groups may be converted by hydrolysis into a carboxy group, esters with tertiary alcohols, e.g. tert.butylesters, may be 26 converted by thermolysis into a carboxy group and esters with aralkanols, e.g. benzyl esters, may be converted by hydrogenolysis into a carboxy group.
The hydrolysis of step is conveniently carried out either in the presence of an acid such as hydrochloric, sulphuric, phosphoric, trichloroacetic or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxane at temperatures between -10 0 C and 320*C, preferably at temperatures between ambient temperature and the boiling :temperature of the reaction mixture. When hydrolysis is carried out in the presence of an organic acid such as trichloroacetic or trifluoroacetic acid, any alcoholic hydroxy groups present may simultaneously be converted into a corresponding acyloxy group such as a trifluoroacetoxy group.
If in a compound of formula V represents a cyano or aminocarbonyl group, such a group may also be converted 1 into a carboxy group with a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, which may simultaneously also be used as solvent, at temperatures between 0 and If in a compound of formula V represents for example a tert.-butyloxycarbonyl group, the tert.-butyl group may also be thermally cleaved, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as ptoluenesulphonic, sulphuric, phosphoric or polyphosphoric acid, conveniently at temperatures between 40*C and 100*C, preferably at the boiling temperature of the solvent used.
27 If R 3 in a compound of formula V represents for example a benzyloxycarbonyl croup, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50*C, more preferably at ambient temperature, under a hydrogen pressure of 1 to 5 bar.
During hydrogenolysis, other groups may be reduced at the same time, e.g. a nitro group may be reduced to the amino group, a benzyloxy group to the hydroxy group, a vinylidene group to the corresponding alkylidene group or a cinnamic acid group to the corresponding phenylpropionic acid group, or they may be replaced by hydrogen atoms, e.g. a halogen may be replaced by a hydrogen atom.
es *a If R 1 in a compound of formula V represents one of the above mentioned hydrolysable groups, it may be converted during the reaction into a corresponding carboxy or amino compound.
Suitable protecting groups for use in step include, for example, triphenylmethyl, tributyl tin and triphenyl tin groups.
The cleaving of a protecting group is preferably carried out in the presence of a hydrohalic acid, more preferably in the presence of hydrochloric acid, in the presence of a base such as sodium hydroxide or alcoholic ammonia in a suitable solvent such as methylene chloride, methanol, methanol/ammonia, ethanol or isopropanol, conveniently at temperatures between 0 and 100'C, preferably at ambient temperature or, if the reaction is carried out in the presence of alcoholic ammonia, at elevated temperatures, e.g. at temperatures between 100 and 28 150°C, preferably at temperatures between 120 and 1400C.
The reaction of step is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150*C, preferably at 125"C.
Appropriately, either the hydrazoic acid is liberated during the reaction from an alkali metal azde, e.g.
sodium azide in the presence of a weak acid such as ammonium chloride, or the tetrazolide salt obtained in the reaction mixture from the reaction with a salt of hydrazoic acid, preferably with aluminium azide or tributyl tin azide, which is also preferably produced in the reaction mixture by reacting aluminium chloride or i: tributyl tin chloride with an alkali metal azide such as sodium azide, is subsequently liberated by acidification with a dilute acid such as 2N hydrochloric or 2N sulphuric acid.
The reaction of step is preferably carried out in a solvent such as tetrahydrofuran or dioxane in the presence of an acid activating agent such as carbonylimidazole at temperatures between 0 and 50 0
C,
0 preferably at ambient temperature.
The catalytic hydrogenation of step is conveniently carried out with hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid at temperatures between 0 and 50*C, preferably at ambient temperature, under a hydrogen pressure of 1 to 7 bar, preferably 3 to 5 bar.
Examples of nucleophilic leaving groups for Z 4 in step include chlorine or bromine atoms, alkoxy or phenylalkoxy groups such as methox'y, ethoxy or benzyloxy groups or, if R 7 represents a hydrocarbon group, a hydroxy group.
29 The reaction of step may conveniently be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary .a organic base such as triethylamine or pyridine, which may simultaneously be used as solvents, conveniently at temperatures between -25 and 150 0 C, preferably at .0 temperatures between -10*C and the boiling temperature of the solvent used.
If Z 4 represents a hydroxy group, however, it is particularly advantageous to c rry out the reaction of step with the reactive derivatives of a carboxylic acid of general formula XI, e.g. with the esters, thioesters, halides, anhydrides or imidazolides.
The reaction of step may conveniently be carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimechylformamide, optionally in the presence of an acid activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus 'trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, or an agent
I
30 30 which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvents, conveniently at temperatures between -25 and 150*C, but preferably at temperatures between -10°C and the boiling temperature of the solvent used.
An ortho-benzamido compound optionally obtained in this way can then, if necessary, be converted into the desired benzimidazole compound by heating, preferably in a solvent or mixture of solvents such as ethanol, e isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycolmonomethylether, diethyleneglycol-dimethylether, sulpholane, dimethylformamide or tetraline, optionally a in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulphuryl chloride, sulphuric acid, p-toluenesalphonic acid, methanesulphonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid, acetic acid anhydride or *i optionally in the presence of a base such as potassium ethoxide or potassium tert.-butoxide. However, this cyclisation may also be carried out without a solvent and/or condensing agent.
The reaction of step may conveniently be carried out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid or propionic acid and/or in an excess of the hydrazine or hydrazine hydrate used, at temperatures between 0 and 200*C, preferably at temperatures between 20 and 150°C, more preferably at the boiling temperature of the reaction mixture, and optionally in the presence of an acid such as sulphuric or p-toluenesulphonic acid as a condensing agent. The reaction may, however, also be carried out without a 31 solvent.
The isomer separation of step is preferably carried out by chromatography using a substrate such as silica gel or aluminium oxide.
The compounds of formula I obtained may, if desired, be converted into the acid addition salts thereof, more particularly for pharmaceutical use the physiologically acceptable salts thereof with inorganic or organic acids. Suitable acids for this purpose include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, lactic, citric, tartaric and maleic O'4, acid.
Furthermore, the new compounds of formula I thus obtained, if they contain a Arboxy or 1H-tetrazolyl group, may, if desired, subsequently be converted into the salts thereof with inorganic or organic bases, more particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable 0*0o40 bases for this purpose include sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
0 0 Some of the compounds of general formulae II to XV used as starting materials are known from the literature.
0 0r Otherwise these compounds may be obtained by methods known from the literature.
Thus, for example, a compound of general formula Il may be obtained by alkylation of a corresponding o-aminonitro compound and subsequent reduction of the nitro group.
Compounds of general formulae III, V, VI, VII, VIII, IX, X, XII or XIV used as starting materials may be obtained 32 by alkylation of a corresponding o-phenylenediamine or a corresponding o-amino-nitro compound, followed by reduction of the nitro group and subsequent cyclisation of an o-diamino-phenyl compound thus obtained, optionally followed by cleaving any protecting group used or by NK-alkylation of a corresponding 1Hbenzimidazole, whilst the isomer mixture thus obtained may subsequently be resolved by conventional methods, e.g. chromatography. Some of the starting compounds mentioned above are described in EP-A-392317.
0 The new compounds of general formula I and the physiologically acceptable salts thereof have valuable pharmacological properties. They are angiotensin antagonists, in particular, angiotensin-JI-antagonists.
Thus in a further aspect the present invention provides a pharmaceutical composition comprising a compound of formula I or a physiologically acceptable salt thereof S" together with at least one pharmaceutical carrier or excipient.
In a still further aspect the present invention provides the use of a compound of formula I or a physiologically 0. acceptable salt thereof for the manufacture of a therapeutic agent for the treatment of hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of cardiac insufficiency progression after myocardial infarct, or for the treatment of diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
In a still yet further aspect the present invention provides a method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory -33 disorders, myocardial ischaemia (angina), cardiac insufficiency progression following myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases, said method comprising administering to said body a compound of formula 1 or a physiologically acceptable salt thereof.
By way of example, the following cnompounds: A =4 '-[[2-n-propyl-6- (l-methylbe:nzimidazol-2-yl) benzimidazol-l-yl]methyl~biphenyl-2-carboxylic acid; B =4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-1-yl]methyl~biphenyl-2-carboxyi.c aciddihydrat-e; C =4'-[[2-n-butyl-6-(2,3-diphenyl-maleic acid imido)benzimidazol-1-yl3methyl ]biphenyl-2-carboxylic acid; D =4 '-[[2-n-butyl-6-(2,3-dimethyl-maleic acid imido) goobenzimidazol-1-yl )methyl) biphenyl-2-carboxylic acid; E =4'-([2-n-butyl-6-(N-phenylmethanesulphonyl- :methylamino) -benzimidazol-l-yl]methyljbiphenyl-2carboxylic acid; F 4 [2-n-butyl-6-(2-oxo-piperidin-i-yl) benz4imi.'dazol-1-yl]methyl]-2- (lH-tetrazol-5-yl) biphenyl; G =4 2-n-butyl-6-(2-oxo-pyrrolidin---yl)benzimidazol-l-yl~imethyl] (lH-tetrazol-5-yl) biphenyl; H 4' [2-n-butyl-6-(2-oxo-hexamethylieneimino) benzimaidazol-l-yl~methyl 3-2- (lH-tetrazol-5-yl) 34 biphenyl; I 4'-[[2-n-butyl-6-(3,3-dimethylglutarimido)biphenyl; J 4'-[[2-n-butyl-6-(N-methylaminocarbonyl-npentylamino)-benzimidazol-l-yl]methyl]-2-(lH- -biphenyl; 4 4. K =4'-[[2-n-butyl-6-(cyclohexylaminocarbonyl-npentylamino)-benzimidazol-l-yl]methyl]-2-(lHtetrazol-5-yl)-biphenyl hydrate; and L 4'-[[2-n-butyl-6-(2-oxo-3,4-tetramethylenepyrrolidin-l-yl)-benzimidazol-l-yl]methyl]biphenyl- 2-carboxylic acid were tested for their biological effects as follows: Rats (male, 180-220 g) are anaesthetised with sodium hexobarbital (150 mg/kg After they have become unconscious, a tracheal cannula is inserted, the animals are pithed and then immediately artificially respirated with a ventilator pump. The arterial blood pressure is 0 recorded by means of a cannula in the carotid artery using a Bell Howell pressure recorder. The substances are administered in the jugular vein through a cannula.
Test substances are administered in three doses (10, -0 and 30 mg/kg with one dose of substah-e being tested on each animal. Three minutes after the intravenous administration of the test substance, angiotensin-II is administered intravenously in increasing doses and in this way a cumulative doseactivity relationship is achieved for angiotensin-II in the presence of the test substances. The increase in I L 35 arterial blood pressure is measured.
These dose-activity curves are compared with standard curves for angiotensin-II without the use of any test substances. Using a computer program, the shift to the right in the dose-activity curves for angiotensin-II as a result of the administration of the test substances are determined and corresponding pA 2 -values are calculated for the test substances.
The pA 2 values of the above-mentioned test compounds A to L are between 6.0 and Moreover, when the above-menticned corpounds were administered in a dose of 30 mg/kg i.v. no toxic side effects, e.g. negative inotropic effects or heart rhythm disorders, were observed. Accordingly, the compounds are well tolerated.
The new compounds and their physiologically acceptable salts are suitable for the treatment of hypertension and cardiac insufficiency and also for treating ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), for the prevention of the progression of cardiac insufficiency after myocardial infarct and for treating diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases.
The new compounds and the physiologically acceptalle salts thereof are also suitable for treating pulmonary diseases, e.g. lung oedema and chronic bronchitis, for preventing arterial re-stenosis after angioplasty, for preventing thickening of blood vessel walls after vascular operations, and for preventing arteriosclerosis and diabetic angiopathy. In view of the effects of angiotensin on the release of acetyl choline and dopamine in the brain, the new angiotensin antagonists 36 are also suitable for alleviating central nervous system disorders, e.g. depression, Alzheimer's disease, Parkinson syndrome, bulimia and disorders of cognitive furction.
The dosage required to achieve these effects is conveniently, when administered intravenously, 20 to 100 mg, preferably 30 to 70 mg, and, when administered orally, 50 to 200 7, preferably 75 to 150 mg, 1 to 3 a t times a day. For this purpose, the compounds of formula I and salts thereof, optionally in conjunction with other active substances such as antihypertensives, diuretics and/or calcium channel blockers, may be incorporated together with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propylene-glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suit ble mixtures thereof, in conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories, Suitable active ingredients for the above-mentioned combinations include for example atenolol, bendroflumethiazide, chlorothiazide, (di)hydra1 alzine hydrochloride, hydrochlorothiazide, metoprolol, prazosin, propranolol, spironolactone, benzthiazide, cyclothiazide, ethacrinic acid, furosemide, diltiazem, felodipine, nicardipine, nifed.pine, nisoldipine and nitrendipine. The individual dosages for these ingredients can range from about one-fifth of the usually minimal recommended dosage up to the maximum recommended dosage, for example from 15 to 200 mg of 4 1 I 37 hydrochlorothiazide, from 135 to 2000 mg of chlorothiazide, from 15 to 200 mg of ethacrinic acid, from 5 to 80 mg of furosemide, from 20 to 480 mg of propranolol, from 5 to 60 mg of felod pine, from 5 to mg of nifedipine or from 5 to 60 mg of nitrendipine.
The following non-limiting Eyamples are provided to illustrate the invention. Unless otherwise specified aill percentages and ratios given are by weight: 0 S 9 38 Example 1 4'-[r2-n-Propyl-5-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid and 4'-[[2-n-Propyl-6-(1-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid a) 0 S*.i A solution of 23.9 g (100 mMol) of methyl 3,4-diaminobenzoate dihydrochloride and 11.7 g (110 mMol) of butyric acid chloride in 100 ml of phosphorus oxychloride is refluxed for 2 hours. Then about 80 ml of phosphorus oxychloride are distilled off and the residue is mixed with about 150 ml of water. The oily crude product precipitated is extracted three times with 50 ml of ethyl acetate and after evaporation purified by column chromatography (600 g of silica gel; eluant: methylene chloride/methanol (30:1 by volume)).
Yield: 15.0 g of oil (69% of theory) b) 2-n-Propyl-benzimidazole-5-carboxylic acidhemisulphate A solution of 15.0 g (73 mMol) of methyl 2-n-propyland 8 g (200 mMol) of sodium hydroxide in 200 ml of water and 400 ml of ethanol is refluxed for 2 hours. Then the alcohol is distilled off, the aqueous solution is acidified with dilute sulphuric acid (pH 4-5) and evaporated using a rotary evaporator. The product crystallising out is suction filtered, washed with 50 ml of acetone and 50 ml of diethylether and dried.
Yield: 9.1 g (61% of theory), Melting point: 220*C.
C
11
H
2
N
2 0 2 O x 1/2 H 2
SO
4 (253.26) Calculated: C 52.17 H 5.17 N 11.06 S 6.33 I i I 39 Found: 51.87 5.23 11.11 6.41 c) 2-n-Prop, '-5-(l-methvlbenzimidazol-2-yl)benzimidazole A solution of 6.7 g (25 mMol) of 2-n-propylacid-hemisulphate and 4.9 g mMol) of 2-methylaminoaniline-dihydrochloride in 200 g of polyphosphoric acid is stirred for 5 hours ot .150°C, then poured onto 600 ml of water and made alkaline with concentrated ammonia whilst cooling with ice. The resulting solution is extracted three times with 200 ml of e'hyl acetate, the crude product thus obtained is purified by column chromatography (300 g of *0 silica gel; eluant: methylene chloride/methanol 15:1 by volume).
Yield: 2.8 g of oil (39% of theory), 18
CH
18
N
4 (290.37) Calculated: C 74.46 H 6.25 N 9.29 Found: 73.92 6.32 18.96 0 d) Tert.-butyl 4'-[[2-n-propyl-5-(l-methylbenzimidazol- 2-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic e.o acid and o 0 0**0 tert.-butyl 4'-[[2-n-propyl-6-(l-methylbenzimidazol- 2-yl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid A solution of 2.0 g (6.9 mMol) of methylbenzimidazol-2-yl)-benzimidazole and 0.91 g mMol) of potassium tert.-butoxide in 50 ml of dimethylsulphoxide is stirred for 90 minutes at ambient temperature, then 2.6 g (7.5 mMol) of tert.-butyl 4'bromomethyl-biphenyl-2-carboxylate are added and the mixture is stirred for a further 15 hours at ambient temperature. The mixture is then poured onto 300 ml of water and extracted three times with 50 ml of ethyl acetate. The crude product obtained after evaporation of the organic phase is puri-ied by column chromatography (300 g sill.ca gel; eluant: methylene chloride/methanol =30:1 by volume). In this way, 2.7 g of theory) of an isomer mixture are obtained, which when analysed by NMR spectroscopy, contains about 1.18 g of tert. -butyl 4 (2-n-propyl-5- (l-methylbenzimidazol- 2-yl) -benz imidazol-1-yl) -methyl]biphenyl-2=-carboxylate and about 1.52 g of tert.-butyl 4'-[(2-n-propyl-6-(lmethylbenzimidazol-2-yl) -benzimidazol-l-yl) -methyl] biphenyl-2-carboxylate.
Rf value: 0.43 (methylene chloride/methanol =19:1 by e) 4 [2-r-Prcpyl-5-(l-methylbenzimidazol-2-yl) benzimidazol--yl]milethyl ]biphenyl-2-carboxylic acid and 4 [2-n-propyl--6-(l-methylbenzimidazol-2-yl) benzimidazol-l-vllmethvlibiphenyl-2-carboxylic acid 2.70 g of the isomer mixture obtained in Example ld are dissolved in 100 ml of methylene chloride, mixed with ml of trifluoroacetic acid and stirred for 4 hours at ambient temperature. The mixture is then evaporated to '.dryness in vacua, the residue is dissolved in 100 ml of 2N sodium hydroxide solution, the solution is washed with 50 ml of diethylether and the product mixture is precipitated by acidifying the aqueous phase with acetic acidi. By column chromatography (400 g of silica gel, eluant: methylene chloride/methanol 15:1 by volume) of the solid thus obtained, 0.7 g (58% of theory) of 4'- [2-n-propyl-5-(l-methylbenzimidazol-2-yl) -benzimidazoll-yl]methyl] -biphenyl-2-carboxylate are obtained, melting point 2l9-220*C
C
32
H
28
N
4 0 2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.54 5.57 11.01 Rf value: 0. 15 (methylene chloride/methanol =9:1 by volume) and, 0.9 g (74% of theory) of 4'-[[2-n-propy2-6-(l- 'I i I -41methylbenzimidazol-2-yl) -benz imidazol-1yl ]methyl) biphenyl-2 -carboxylate are obtained, melting point 217-218*C C 32
H
28
N
4 0 2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.63 5.55 11.29 Rf value: 0.40 (methylene chloride/methanol =9:1) The following compounds are obtained analogously: 4 [2-n-propyl-6-(1, 6-dimethyl-benzimidazol-2-yl) 0* 4 benzimidazol-l-yl]xnethyl]biphenyl-2-carboxylic acid *6 4' [2-n-butyl-6- (l-methyl-5-bromo-benzimidazol-2-yl) benzimidazol-l-yl ~methyl] biphenyl-2 -carboxylic acid 4 [2-n-butyl-6-(l-methyl-5-methoxy-benzimidazol-2-yl) benzimnidazol-l-yl]inethyl]biphenyl-2-carboxylic acid 4 [2-n-butyl-6- benzimidazol-2-yl) -benzimidazol-l-yllmethyl]biphenyl-2carboxylic acid [[2-n-butyl-6- (1-n-hexyl-5-mnethyl-benzimidazol-2-yl) se 4. benzimidazol--yljmethyl]biphenyl-2-carboxylic acid 4 '-t[2-n-propyl-6-(l-methyl-5-fluoro-benzimidazol-2-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4 [2-n-propyl-6-(l-mothyl-5-chloro-benzimidazol-2-yl) benzimidazol-1-yllmethyl.]biphenyl-2-carboxylic acid I I I I -42- Examjp.Le 2 4' [2-n-Butyl-6- (l-methylbenzimidazol-2-yl) benzimidazolA-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [2-n-butyl-6- (l-methylbenzimidazol-2-yl) -benzimidazoll-yl ]methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 43% of theory, melting point: amorphous C 33
H
30
N
4 0 2 (514.60) Calculated: C 77.02 H1 5.88 N 10.89 OS*Found: 76.88 5.83 10.55 R f~ value: 0.42 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) Mass spectrum: (M4 515 Example 3 4' (Biphenyl-4-carbonylamino) -2-n-butyl- 5 benzimidazol-1-yl]methyl]bipheiyl-2-carboxylic acid x 0.25 1120 Prepared analogously to Example 1 from tert.-butyl 4'- (biphenyl-4-carbonylamnino) -2-n-butyl-benzimidazol-lyl ]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
:Yield: 70.6% of theory, Melting point: 316-317'C
C
38
H
33
N
3 0 3 X 0.25 1120 (584.20) Calculated: C 78.13 H 5.78 N 7.19 Found: 78.12 5.79 7.08 R f value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) -43- Bqtample 4 4'1- (Biphenylyl-4-aminocarbonyla-mino) -2 -n-butylbenzimidazol-1-yl~methyl ]biphenyl-2-carboxylic acid trifluoroacetate-semihydrate Prepared analogously, to Example 1 from tert.-birtyl 4'- (biphenylyl 4-aminocarbonyl amino) -2-n-butylbenzimidazol-1-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 97.0% of theory, Melting point: 171-172*C
**C
3 8
H
3 4
N
4 0 3 X CF 3 CQOH x 1/2 H 2 0 (717.74) 5: Calculated: C 66.94 H 5.06 N 7.81 :Found: 67.13 4.99 7.76 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) Example **see: (6 -Benz enesulphonamido- 2-n-butyl -ben zimida zol 1-yl) 5 methyl] biphenyl-2-carboxylic acid Prepared analogously to Example I from tert.-butyl 4'- (6 -ben zenesulphonamido-2 -n-butyl -ben zimida zol -1-yl) methyl] biphenyl -2 -carboxyl ate and tri fluoroacetic acid in methylene chloride.
Yield: 75.0% of theory, :Melting point: 251-252*C
C
31 H 29
N
3 0 4 F' (539.65) Calculated: C 69.00 H 5.42 N 7.79 S 5.94 Found: 68.96 5.52 7.82 5.86 Rfvalue: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia =50:45:5) .9 -44- Example 6 4 (N-,Benzenesulphonyl-methylamino) -2-n-butylbenzimidazol-l-yl ]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- (N-benzenesulphonyl-methylamino) -2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methy-lene chloride.
Yield: 70.0% of theory, Melting point: 211-2l2*C
C
32
H
31
N
3 0 4 S (553.68) seeCalculated: C 69.42 H 5.64 N 7.59 S 5.79 *:Found: 69.24 5.66 7.53 6.02 :Rf value: 0. 55 (silica gel; eluant: ethyl I.f acetate/ethanol/ammonia 50:45:5 by volume) Example 7 [2-n-Butyl-6- (cyclohexylmethylaminocarbonylamino) see**:benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid- 4 11tri fluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (cyclohexylmethylaminocarbonylamino) benzimidazol-l-yl]methyl~biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 91.1% of theory, 0 Melting point: 149-150*C
C
33
H
38
N
4 0 3 X CF 3 COOH (652.71) Calculated: C 64.41P H 6.02 N 8.58 Found: 64.23 6.09 8.73 Rf value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) I I I' I Example 8 4 [[2-n-Butyl-6- (N-cyclohexylmethyl-acetamido) benzimidazol-l-yl~methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [2-n-butyl-6- (N-cyclohexylmethyl-acetamido) benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 78.6% of theory, Melting point: 185-187*C C 34
H
39
N
3 0 3 (537.70) Calculated: C 75.95 H 7.31 N 7.81 SO*Found: 75.75 7.40 7.65 Rf value: 0.45 (silica gel; eluant: ethyl acetate/ethanol/am-monia 50:45:5 by volume) Example 9 4 (Bicyclkohexyl-4-carbonylamino) -2-n-butylbenzimnidazol-l-yl]methyl]biphenyl-2-carb~oxylic acid 5 trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- (bicyclohexyl-4-carbonylamino) -2-n-butylbenzi-midazol-l-yl ]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
e *Yield: 93.3% of theory, Melting point: 104-106'C
C
38
H
45 N 3 0 3 x CF 3 CO0H (705.82) Calculated: C 68.07 H 6.57 N 5.95 Found: 68.38 6.64 5.80 R f value: 0.30 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) I I I -46- Example 4' (Bicyclohexyl-4-aminocarbonylamino) -2-n-butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid semitri fluoroacetate-monohydrate Prepared analogously to Example 1 from tert.-butyl 4'- (bicyclohexyl-4-aminocarbonylamino) -2-n--butylbenzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 94.9% of theory, Melting point: 119-120'C
C
38
H
46
N
4 0 3 x 1/ 2 CF 3 COOH x H 2 0 (681.83) *Calculated: C 68.70 H 7.17 N 8.22 :Found: 68.32 6.91 7.81 SRf value: 0.30 (silica gel; eluant: ethyl f acetate/ethanol/ammonia 80:40:2 by volume) Example 11 *too*:4 '-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)- 5 benzimidazol-l--yl]methyl]biphenyl-2-carboxylic acid 0* dihydrate of* Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-1',uLtyl-6- 6-tetrahydro-phthalimino) benzi~iidazol-l-y1]methyl ]biphenyl-2-carboxylate and .5 trifluoroacetic acid in methylene chloride.
:Yield: 14.7% of theory, Melting point: 119-122'C
C
33
H
31
N
3 0 4 x 2 H 2 0 (533.63) Calculated: C 69.58 H 6.19 N 7.38 Found: 69.77 6.34 7.65 Rf value: 0.45 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) I I f I -47- Example 12 [2-n-Butyl-6- suilphonainino) -benzimidazol-l-yl jmethyl~biphenyl-2carboxylic acid-semitrifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-'butyl-6- suiplhonamino) -benzimidazol-l-yl ]methyl]biphenyl-2carbc'xylate and trifluoroacetic acid in methylene chloride.
Yield: 92.3% of theory, Melting point: 148-150*C
:C
3 7
H
36
N
4 0 4 S x 1/2 CF 3 COOH (689.78) :Calculated: C 66.17 H 5.33 14 8.12 S 4.64 Found: 65.40 5.33 7.92 5.19 Example 13 4 2-n-Butyl-6-(2,3-diphenyl-maleic acid imido)benzimidazol-l-yl]methyl ]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n--butyl-6- 3-diphenyl-maleic acid imido) '**benzimidazol-l-yl]methyljbiphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: C02.6% of theory, Melting point: 236-237*C
.:C
41
H
33
N
3 0 4 (631.73) Calculated: C 77.95 H 5.27 N 6.65 Found: 77.66 5.24 6.56 Rf value: 0. 65 (silica gel; eluant: ethyl acetate/ethanol/ammonia 50:45:5 by volume) -48- Exainp1e 14 4 2-n-Butyl-6- (N-methanesulphonyl-2-phenylethylamino) -benzimidazol-l-yl]meth,'yl]biphenyl-2-carboxylic acj-d Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (N-methanesulphonyl-2-phenylethylamino) benzimidazolP4-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 71.4% of theory, Melting point: 215-216*C Sep C 34
H
35
N
3 0 4 (581.73) Calculated: C 70.20 H 6.06 N 7.22 S 5.51 See. Found: 69.99 6.14 7.23 5.55
R
1 value: 0.25 (silica gel; eluant: ethyl C acetate/ethanol/ammonia =80:40:2 by volume) Example 4 [2-n-Butyl-6-(2,3-di-methyl-maleic acid imido) benzimidazol-l-yl]methyllbiphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- 3-dime,:thyl-maleic acid imido) benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
VS640 Yield: 69.6% of theory, See: Melting point: 289-290'C
C
31
H
29
N
3 0 4 (507.59) Calculated: C 73.35 H 5.76 N 8.28 Found: 73.14 5.90 8.20 Rf value: 0. 55 (silica gel; eluant: ethyl acetate/ethanol/ammonia 50:45:5 by volume) I I r 1, .49 Example 16 4' -[[6-(N-Benzenesulphonyl-ri-pentylamino) -2-n-butylbenzimnidazol-l-yl]methyl]biphenyl-2-carboxylic acid Pr'qpared analogously to Example 1 from tert.-butyl 4'- (N-benzenesulphonyl-n-pentylamino) -2-n-butylbenzimidazol-l--yl]methyl]biphenyl-2-carboxylate and tri fluoroacetic acid in methylene chloride.
Yield: 83.9% of theory, Melting point: 243-244 0
C
Q
36
H
39
N
3 0 4 S (609.78) Calculated: C 70.91 H 6.45 N 6.89 S 5.26 0. F'ound: 70.92 6.21 6.98 5.19 :Rf value: 0.45 (silica gel; eluant: ethyl ease*: acetate/ethanol/ammonia =80:40:2 by volume) Example 1437 2-n-Butyl-6- (N-4-methoxybenzenesulphonyl-npentyla-mino) -benzimidazol-l-yllmethyl]biphenyl-2carboxylic acid Prepared analogously to Examp e 1 from tert. -butyl 4 :a, 0 se -n-butyl-6- (N-4-methoxybenzenesulphonyl-np(ekntylamino) -benzimidazol-1-yl 3methyl] biphenyl-2- Larboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.6% of theory, 0.
Melting point: 207-208*C
C
37
H
41
N
3 0 5 S (639 .81) Calculated: C 69.46 H 6.46 N 6.57 S 5.01.
Found: 69.31 6.50 6.77 5.21 Rfvalue: 0.50 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) I i I I 50 Example 18 4 '-rF[2-n-Butyl-6- (N-4-chlorobenzenesulphonylmethylamino) -benzimidazol-1-yl]methyl~biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl1-6- (N-4-chlorobenzenesulphonyl-methylamino) benzimidazol-1-yl]methyl~biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 84.E' of theory, Melting point: 240-2d41*C 32
H
30 C1N 3 0 4 S (588.12) .:Calculated: C 65.35 H 5.14 N 7.14 Cl 6.03 S 5.45 :Found: 65.02 5.30 7.17 6.21 5.46 Example 19 4 [[2-n-Butyl-6- (N-phenylmethanesulphonyl-methyla-mino) benzimidazol-l--yl]methyl~biphenyl-2-carboxylic acid *see*:Prepared analogously to Example 1 from tert.-butyl 4' [[2-n-butyl-6- (N-phenymethanesulphonyl-methylamino) benzimidazol-l-yljmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 54.9% of theory, Melting point: 208-209*C 33
H
33
N
3 0 4 S (567.70) ~.Calculated: C 69.82 H 5.86 N 7.40 S 5.65 Found: 69.54 5.79 7.47 5.59 I I I I 51 Example 4 [[2-n-Butyl-6- (N-4-methylbenzenesulphonylmethylamino) -benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- 2-n.-butyl-6- 4-methylben ienesulphonyl -me-thyl amino) benzimidazol-l-yl )methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 92.5% of theory, Melting point: 259-260*C C 33
H
33
N
3 0 4 S (567.70) Calculated: C 69.82 HI 5.86 N 7.40 S 5.65 .:Found: 69.70 5.90 7.44 5.68 Rf value: 0. 25 (silica gel; eluant: ethyl f acetate/ethanol/ammonia =80:40:2 by volume) Example 21 4' -[[2-n-Butyl-6- (N-n-propylsulphonyl-methylamino) benzimidazol-l-yl]methyl~biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'boo [[2-n-butyl-6- (N-n-propylsulphonyl-methylamino) benzimidazol-l-yl]methy-,]biphenyl-2-carboxylate and trifluoroacetic acid in mathylene chloride.
Vote, Yield: 67.3% of theory, Melting point: 222-223'C C 29
H
33 N 3 0 4 S (519.66) Calculated: C 67.03 H 6.40 N 8.09 S 6.17 Found: 67.02 6.49 8.04 6.18 R f value: 0.20 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) I I; I r 52 Example 22 4' -[2-n-Butyl-6- (N-4-methoxybenzenesulphonyl-npropylamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid Preparea analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6-(N-4-methoxybenzenesulphonyl-npropylamino)-benzimidazol-l-yl]methyl bipheny -2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86.4% of theory, 44 C Melting point: 227-228C S. C 35
H
37
N
3 0 5 S (611.75) Calculated: C 68.72 H 6.10 N 6.87 S 5.24 Found: 68.54 6.20 6.88 5.25 R value: 0.25 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) Example 23 4'-[[2-n-Butyl-6-(N-4-methylbenzenesulphonyl-npropylamino) -benzimidazol-l-yl Imethyl hiphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- :[2-ii-butyl-6-(N-4-methylbenzenesulphonyl-n- 44 SS propylamino)-benzimidazol--yl]methyl]biphenyl-2carboxylic acid and trifluoroacetic acid in methylene chloride.
Yield: 82.8% of theory, Melting point: 223-224 0
C
C
35
H
37
N
3 0 4 S (595.76) Calculated: C 70.56 H 6.26 N 7.05 S 5.38 Found: 70.25 6.20 7.24 5.61 Rf value: 0.29 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) I I I I -53 Example 24 4' [2-n-Butyl-6- (N-4-chlorobenzenesulphonylisopropylamino) -benz imidazol-1-yl ]methyl ]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [2-n-butyl-6- (N-4-chlorobenzenesulphonylisopropylamino) -benzimidazol-l-yl~methy1]biphenyl.-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 82.1% of theory, Melting point: 260-261'C
C
34
H
34 C1N 3 0 4 S (616. 17) :Calculated: C 66.28 H 5.56 N 6.82 Cl 5.75 S 5.20 Found: 66.05 5.77 7.05 5.87 5.34 *Rf value: 0.30 (silica gel; eluant: ethyl **acetate/ethanol/ammonia =80:40:2 by volume) Example *4 (N-Benzoyl-isopropyla-mino) -2-n-butylbenzimidazol-l-yllmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- (N-benzoyl-isopropylamino) -2-n-butyl-benzimidazol-lyl] -methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
:Yield: 58.3% of theory, Melting point: 209-210*C
C
35
H
35
N
3 0 3 (545. 68) Calculated: C 77.04 H 6.46 N 7.70 Found: 76.66 6.57 7.65 Rf value: 0. 20 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) I I I -54- Example 26 4'-[[2-n-Butyl-6-(lH,3H-quinazolin-2,4-dion-3-yl)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid hemihydrate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6-(lH,3H-quinazolin-2,4-dion-3-yl) benzimidazol--yl]nethy] bipheaiyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 53.1% of theory, Melting point: 338-340*C
**C
3 3
H
2 8
N
4 0 4 x 1/ 2 H 2 0 (553.61) :Calculated: C 71.59 H 5.28 N 10.12 00 Found: 71.19 5.33 10.22 0 Example 27 4' [2-n-Butyl-6- (N-4-chlorobenzenesulphonylbenzylamino) -benz imidazol-l-yl Imethyl ]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (N-4-chlorobenzenesulphonyl-benzylamino) benzimidazol-1-y1]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 64.5% of theory, Melting point: 212-213*C
C
38
H
34 C1N 0S (664.22) Calculated: C 68.72 H 5.16 N 6.33 Cl 5.34 S 4.83 Found: 68.76 5.27 6.39 5.62 4.81 Rf value: 0. 28 (silica gel; eluant: ethyl acetate/ethanol/ammonia =80:40:2 by volume) I I I I Example 28 4' (2-n-Butyl-6- (N-n-butanesulph1-.,'yl -benzyl amino) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 froia tert.-butyl 4'- I 2-n-butyl-6- (N-n-butanesulphonyl-benzylamino) benzimidazol-1-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 66.4% of theory, Melting point: 193-194'C
C
36
H
39
N
3 0 4 S (609.78) Calculated: C 70.91 H 6.45 N 6.89 S 5.26 Found: 70.76 6.54 6.94 5.40 vwdue: 0.25 (silica gel; eluant: ethyl see**:acetate/ethanol/ammonia 80:40:2 by volume) Example 29 [2-n-Butyl-6- 7-dimethoxynaphthalen-2-sulphonylmethylamino) -benzimidazol-l-yl]methyl]biphenyl-2carboxylic. acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (N-6 ,7-dimethoxynaphthalen-2-sulphonylmethylamino) -benzimidazol-l--yl]methyl]biphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 87.0% of theory, Melting point: 261-262'C
C
38
H
37
N
3 0 6 S (663.79) Calculated: C 68.76 H 5.62 N 6.33 S 4.83 Found: -'69.00 6.00 6.15 5.07 Rf value: 0.23 (silica gel; eluant: ethyl acetate/ethanol/ammonia 80:40:2 by volume) -56- Example [[2-n-Butyl-6- (2-oxo-3 ,4-tetramethylene-pyrrolidin-lyl) -benzimidazol-l-yl]methyl]biphenyl-2-carhoxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (2-oxo-3, 4-tetramethylene-pyrrolidin-lyl) -benz imidazol-l-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 38.0% of theory, Melting point: 146-148'C C 33
H
33
N
3 0 3 (519.65) a Rf value: 0.30 (silica gel; eluant: methylene :chloride/ethanol =9:1 by volume) Example 31 "S [2-n-Butyl-5- (2-oxo-3, 4-tetramethylene-pyrrolidin-lyl) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- (2-oxo-3, 4-tetramethylene-pyrrolidin-lyl) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
S Yield: 15.5% of theory, Melting point: amorphous
C
33
H
33
N
3 0 3 (519.65) Rf value: 0.20 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) -57- Example 32 4 '-[[2-n-in-utyl-6- 3-dimethylpiperidin-l-yl) benzimidazol-l-yljmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6- (3 ,3-dimethylpiperidin-l-yl) -benz imidazol- 1-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 86% of theory, Melting point: from 120'C (sintering)
C
32
H
37
N
3 0 2 (495.70) U..Calculated: C 77.54 H 7.52 N 8.48 lwFound: 77.54 7.24 8.19 :Rf value: 0.35 (silica gel; eluant: methylene *chloride/ethanol 9:1 by volume) 0~ *'Example 33 4'-1 [2-n-Butyl-6-heptamethyleneimino-benzimidazol-l-yl3methyl Jbiphenyl-2-carboxylic acid S 6 Prepared analogously to Example 1 from tert.-butyl 4'- (2-n-butyl-6-heptamethyleneimnino-benzimidazol-l-yl] 0 **methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 71% of theory, Melting point: 195-198'C *1 C 3
H
3 N (495.60) OCalculated: C 77.55 H 7.52 N 8.48 Found: 77.40 7.66 8.23 Rf value: 0.40 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) I I I I 58 Example 34 [2-n-Butyl-6- (pi4peridin-l-yl) -benzimidazol-lyl~rmethyl]bi-ohenyl-2-carboxylic acid Prepared analogously to Example 1 from tert 'utyl 4'- [[2-n-butyl-6- (piperidin-l-yl) -benz imidazolyl]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 84% of theory, Melting point: 199-200*C H CH 3 No0 (467.60) Calculated: C 77.06 H 7.11 N 8.99 '..Found: 76.85 7.28 9.02 Rf. value: 0. 40 (silica gel; eluant: methylene SS chloride/ethanol 9:1 by volume) Example 4 [2-n-Butyl-6-(4-methylpiperidin-l-yl)--benzimidazol- 1-yl~methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'a*e [[2-n-butyl-6- (4-methyl-piperidin---yl) -benzimidazol-lyl]methyl]biphenyl-2-carboxylate and trifluoroacetic :Got**acid.
Yield: 82% of theory, 0* Melting point: 162-165*C
C
31
H
35
N
3 0 2 (481.60) Calculated: C 77.31 H 7.33 N 8.73 Found: 77.20 7.19 8.63 Rf value: 0.40 (silica gel; eluant. Tinethylene chloride/ethanol 9:1 by volume) -59- Example 3 6 4' [2-n-Butyl-6-hexamethyleneimino-bexzimidazol-1-y methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 41- [(2-n-butyl-6-hexamethyleneimino-benzimidazol-l-yl) methyl] -biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 34% of theory, Melting point: 197-199*C
C
3 1
H
35
N
3 0 2 (481.60) Calculated: C 77.31 H 7.33 N 8.73 *Found: 76.99 7.35 8.62 0* Rf value: 0.40 (silica gel; eluant: methylene *Vof:chloride/ethanol =9:1 by volume) 0 s Example 37 4' [2-n-Propyl-6- (2-oxo-piperidin-l-yl) -benzimnidazol-lyl Imethyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6-(2-oxo-piperidin-l-yl) -benzimidazol-lyl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid.
**Yield: 60% of theory, Melting point: 208-2l0*C Os.C 29
H
29
N
3 0 3 (467.60) Calculated: C 74.49 H 6.25 N 8.99 Found: 74.00 6.29 8.90 Rf value: 0. 50 (silica gel; eluant: methylene chloride/ethanol =9:1 by volume) I I I 60 Examp~le 38 4' [2-n-Propyl-6- (propanesultam-l-yl) -benzimidazol-lyl Imethyl ]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6- (propanesultam-1-yl) -benz imidazol-lyl ]methyl] biphenyl-2-carboxylate and trifluoroacetic acid.
Yield: 49% of theory, MeltinS point: amorphous.
C
27
H
27 N,'0 4 S (489.58) **Calculated: C 66.23 H 5.56 N 8.56 S 6.55 0*.Found: 66.08 5.50 8.37 6.51 Rf.' value: 0. 47 (silica gel; eluant: -methylene ***chloride/ethanol 9:1 by volume) Mass spectrum: (M 490 Example 39 2-n--Propyl-6-(butanesultakm-l-yl) -benzimidazol-lyl ]methyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6- (butanesultam-l-yl) -benzimidazol-lyl Imethyl] biphenyl-2--carboxylate and trifluoroacetic acid.
Yield: 57% of theory, Melting point: amorphous
C
28
H
29
N
3 0 4 S (503. 63) Calculated: C 66.77 H 5.80 N 4 S 6.37 Found: 66.59 5.77 18 6.33 Rf value: 0.51 (silica gel; eluant: methyl.ene chloride/ethanol =9:1 by volume) Mass spectrum: (M 504 I I 61- Example 4' [2-n-Butyl-6-(butanesultam-1-yl) -benzimidazol-lyl Jmethyl] biphenyl-2--carboxylic acid Prepareil analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6-(butanesultam-l-,yl) -benzimidazol-lyl]methyl]biphenyl-2-carboxylate and tri.luoroacetic acid.
Yield: 51% of theory, Melting point: 203-205*C
C
2 9
H
3 1
N
3 0 4 S (517.63) Calculated: C 67.29 H 6.04 N 8.12 S 6.19 Found: 67.22 5.97 7.97 6.10 09009:Rf value: 0.52 (silica gel; eluant: methylene to chloride/ethanol 9:1 by volume) Mass spectrum: (M 518 Examt'le 41 *6S~ 4' [2-n-Butyl.-6-(benzoxazol-2-yl) -benzimidazol-lyl]methyl] (lH-tetrazol-5-yl) -biphenyl 0 to a) 2-n-Butvl-5- (benzoxazol-2-yl) -benzimidazole Ves66 1.43 g (12 nMIol) of thionyl chloride are added dropwise at l0*C with stirring to a suspension of 2.52 g mMol) of 2-n-butyl-benzimidazole--5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixbure is heated to 1400C for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant: methylene chloride 3% ethanol).
I I I i 62 Yield: 1.2 g (41% of theory), Melting point: 118-1200C
C
1
HNO
3 0 (291.36) Calculated: C 74.20 H 5.88 N 14.42 Found: 73.98 5.97 14.20 b) Isomer mixture of 4'-[2-n-butyl-6-(benzoxazol-2-yl)-benzimidazol-lyl]methyl]biphenyl-2-carboxylic acid nitrile and 4 '-[[2-n-butyl-5-(benzoxazol-2-yl)-benzimidazol-1yllmethyllbiphenyl-2-carboxvlic acid nitrile A solution of 1 g (3.43 mMol) of (benzoxazol-2-yl)-benzimidazole and 0.98 g (3.60 mMol) of 4'-bromomethyl-biphenyl-2-carboxylic acid nitrile in 20 ml dimethylsulphoxide is mixed with 0.41 g (3.6 mMol) of potassium tert.-butoxide and stirred for 48 hours at ambient temperature. The mixture is then poured onto 100 ml of water, saturated with sodium chloride and extracted three times with 20 ml of ethyl acetate. Ly column chromatography (200 g of silica gel; eluant: .me.
ethyl acetate/petroleum ether (1:1 by voluime)) 1.4 g of theory) of a mixture of the isomers is obtained 4 'in the ratio 1:1 and this mixture begins to sinter from 130*C.
C
32
H
26
N
4 0 (482.59) Calculated: C 79.64 H 5.43 N 11.61 Fcund: 79.64 5.36 11.59 c) 4 '-[[2-n-Butyl-6-(benzoxazol-2-yl)-benzimidazol-1yl methyll-2-(1H-tetrazol-5-l)-biphenyl A solution of the isomer mixture of butyl-6-(benzoxazol-2-yl)-benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid nitrile and 4'-[[2-n-butyl-5- (benzoxazol-2-yl)-benzimidazol-l-yl]methyl3biphenyl-2carboxylic acid nitrile in 20 ml of dimethylformamide is mixed with 2 g of ammonium chloride and 2 g of sodium azide and heated to 120-130*C for 4 hours. After a further 2 g of ammonium chloride and 2 g of sodium azide have been added and the mixture has been heated to -63 120-l30*C for a further 18 hours, it is poured onto 100 ml of water. The product mixture precipitated is suction filtered and separated by coluzin chromatography (300 g of silica gel, eluant: methylene chloride 3% ethanol).
Yield: 100 mg (20% of theory) in amorphous form.
C 32 1T 27
N
7 0 (525.62) Calculated: C 73.12 1; 5.18 N 118.66 Found: 73.10 5.50 18.42 Rf value: 0.75 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) The following compounds are obtained analogously to Example 41: 4 [2-n--butyl--6-(4 ,5-dihydro-2H-pyridazin-3-on-6-yl) benziinidazol-1-yl]methyl] -2-(lH-tetrazol-5-yl) -biphenyl 4 [[2-n-propyl-6- 5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-1-yljmethyl] (lH-tetrazol--yl) -b,,iphenyl [2-ethyl-6-(4,5--dihydro-2H-pyridazin-3-on-6-yl)benzimidazol-l-yl]methyl] (lH-tetrazol-5-yl) -biphenyl 4 [2-n-butyl-6- (2H-pyridazin-3-on-6-yl) -benzimidazol- .0 l-yl]methyl 3-2- (llH-tetrazol-5-yl) -bipheriyl 4 [2-n-propyl-6--(2H-pyridazin-3-on-6-yl) -benzimidazol- L-yl]mnethyl] (lH-tetrazol-5-yl) -biphenyl 4 '-[[2-ethyl-6-(2H-pyridazin-3-on-6-yl) -benzimidazol-lyl~methyl] (1H-tetrazol-5-yl) -biphenyl 4' -E[2-n-propyl-6- (2-methyl-4 ,5-dihydro-pyridazin-3-on- 6-yl) -benzimidazol-1-y13 methyl) (lH-tetrazol-5-yl) biphenyl 4' -n-propyl-6- (2-benzyl-4 ,5-dihydro--pyridazin-3-on- 6-yl) -benzimidazol-1-yljmethyl)-2- (lH-tetrazol-5-yl) -64 biphenyl 4' [2-n-butyl-6- (1-iethyl-iiidazolin-2-yl) benzi~midazol-1-yl]methyl)-2- (lH-tetrazol-5-yl) -biphenyl 4 [2-n-propyl-6-(3'-n-hexyl-imidazoin-2-yl) benzimidazol-1-yl]methyl] (1H-tetrazol-5-yl) -biphenyl 4 '-f(2-n-butyl-6-(J.-n-butyl-imidazolin-2-yl) benzimnidazol-1-yl]methyl]-2-(1H-tetrazol-5-yl) -biphenyl *0 t [2-n-propyl-6- (1-cyclop7 1 opyl-imidazolin-2-yl) NT benziiiazol-1-yl]methy1] (lH-tetrazol-5-yl) -biph~anyl I 4' [2-ni-propyl-6-(1-cyclohexyl-imidazolin-2-yl) *ez~nd 011y~ehl-2(Ht,:~ol5y)bpe 4 [2-n-pvopyi-6- (1-methyl-imidazol-2-yl) -benzimidazoll- 1-yl]methyl3 (1H-tetrazol-5-yl) -bipheny1 6 of 4 2-n-butyl-6-(l-methyl-imidazol-2-yl)-benzimidazols 0 4 [2-n-propyi--6- (1-n-propyl-imidazol-2-yl) benzimidazol-1-yl)rnethyl] (lH-tetrazol-5-yl) -biphenyl as so r 2-n-propyl-6- (1-r-hexy1-imidazol-2-y1) benzimidazol-1-yljmethyl] (lH-tetrazol-5-y -biphenyl 4' -([2-n-but,,1-6-(l-n-butyl-iridazol-2-yl) -beniimidazol- 4' -([2-n-propyl-6- (1-cyclopropyl-ixnidazol-2-yl) benzimidazol-1-yl]methyl] (1H-tetrazol-5-y,) -biphenyl 4' [2-n-propyl-6-(1-cyclohexyl.-imidazol-2-yi) benzimidazol-1-yl]methyl]-2- (1H-tetrazol-5-yly -biphenyl I I I I Example 42 4' [2-n-Propyl-5-(l-methylbenzimidazol-2-yl) benzimidazol-1-yl~methyl] (lH-tetrazol-5-yl) -biphenyl and [2-n-propyl-6- (l-xnethylbenzimiid&Lo1-2-yl) benzimidazol-1-yl]methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from a mixture of 4'- (1-methylbenzimidazol-2-y1) -benzi-midazol- 1-yl]-methyl]biphenyl-2-carboxylic acid nitrile and 4'- [[2n-propyT6-(lmethybenzimidazol-2-yl)benimidazol- 1Sl-ehlbpenl2croyi acdntr n sodium azide in dimethylformamide.
Yield: 29% of theory, Melting point: amorphous
C
32
H
28
N
8 (524.61) Calculated: C 73.26 H 5.38 N 21.36 eae:Found: 73.03 5.22 21.26 *Mass spectrum: (M H)4' 525 6-isomer: Yield: 34% of theory, Melting point: 198-200*C H CH 2
N
8 (524.61) Calculated: C 73.26 H 5.38 N 21.36 Found: 73.11 5.27 21.19 Mass spectrum: (M 525 I I I I -66 Example 43 4 [2-n-ButyJ.-6- (l-methylbenzimidazol-2-yl) benzimidazol-l-yl]methyl]-2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-,[[2-n-butyl- 6- (l-methylbenzimidazol-2-yl) -benzimidazol-,l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 28% of theory, Melting point: 224-226*C C 33
H
30
N
8 (538.63) *Calculated: C 73.58 H 5.61 N 20.81 *.Found: 73.31 5.73 19.99 R~ f value: 0.76 (silica gel; eluant: methylene eschloride/ethanol =9:1 by volume) Mass spectrum: (M 539 Example 44 [2-n-Butyl--6-(2-oxo-piperidin-l-yl) -benzimidazol-lyllmethyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl- 6- (2-oxo-piperidin-l-yl) -benzimidazol-l-yl] 0 methyllbiphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
V06% Yield: 20% of theory, so Melting point: amorphous
*C
30
H
3 jN 7 0 (505.63) Calculated: C 67.94 H 6.23 N 17.33 Found: 67.67 6.13 17.52 R f value: 0.30 (silica gel; eluant: methylene chloride/ethanol =9:1 by volume) -67 Example 4'-r[2?-n-Butyl-6- 3-dimethylpiperidin-l-yl) benzimidazol-1-yl] -methyl] (lH-tetrazol-5-y'l) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl- 6- 3-dimethylpiperidin-l-yl) -benz imidazol-l-yl] methyl]-2-carboxylic acid nitrile and sodium azide in direthylf ormamide.
Yield: 8% of theory, Melting point: sintering from 14800 32H317X HCl (519.70) Mass spectrum: (M H) 4 520 Example 46 4'-r [2-n-Butyl-6- (4 ,4-tetramethyleneglutarimido) 0* benzimidazol-l-yl] -methyl] -4-chloro-2- yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl- 6- 4-tetramethyleneglutarimido) -benzimidazol-l-yl] methyl] -4-chloro-biphenyl-2-carboxylic acid nitrile and 00 sodium azide in dimethylformamide.
Yield: 40% of theory, Melting point: sintering fromr 16000
C
34
H
34
N
7 0 2 C (608 .16) Calculated: C 67.15 H 5.64 N 16.12 *Found: 66.90 5.86 15.86 *.Rf value: 0.50 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) Example 47 [2-n-Butyl-6- (propanesultam-l-yl) -benz imidazol-lyl] -methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl- 6- (propanesultam-l-yl) -benzimaidazol-l-yl)methyl]biphenyl-2-carboxylic acid nitrile and -68dimethyl formamide.
Yield: 46% of theory, Melting point: 203-205*C C 28
H
29
N
7 0 2 S (527.70) Calculated: C 63.73 H 5.54 N 18.58 S 6.08 Found: 62.52 5.56 18.40 6.00 Rf value: 0. 35 (silica gel; eluant: methylene chloride/ethanol =9:1 by volume) Example 48 4' [2-n-Butyl-6-(butanesultam-1-yl) -benzimidazol-l-yl] methyl] (lH-tetrazol-5-yl) -biphenyl e e
S
Prepared analogously to Example 41 from 4'-[[2-n-butylofof 6- (butanesultam-l.-yl) -benzimidazol-l-yl]ego**:methyl]biphenyl-2-carboxylic acid nitrile and sodium fee* azide in dimethylformamide.
Yield: 30% of theory, Melting point: 189-191*C CzqH 31 N70 2 S (541.70) Calculated: C 64.30 H 5.95 N 18.10 S 5.92 Found: 64.40 5.75 17.90 5.85 R f value: 0.37 (silica gel; eluant: methylene chloride/ethanol =9:1 by volume) off Example 49 of* 4 [2-n-Propyl-6-(butanesultam-l-yl) -benzimidazol-lyl] -methyl] Prepared analogously to Example 41 from 4'-[[2-n-propyl- 6- (butanesultam-l-yl) -benzimaidazol-l-yl]methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 37% of theory, Melting point: 204-206*C
C
28
H
29
N
7 0 2 S (527.63) Calculated: C 63.73 H 5.54 N 18.58 S 6.08 Ii I 69 Found: 63.70 5.49 18.37 6.19 Rf value: 0.36 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) Mass spectrum: m/e =527 Example Mixture of [2-n-butyl-6- (2-hydroxy-cyclohexylaminocarbonyl) benzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl and 4 (2-hydroxy-cyclohexylaminocarbonyl) benzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyl so Prepared analogously to Example 41 from a mixture of 4'- [[2-ni-butyl-6-(2-hydroxy-cyclohexylaminocarbonyl) *Does:benzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid nitrile and 2-n-butyl-5- (2-hydroxy-cyclohexylaminocarbonyl) -benz imidazol-l-yl] -methyl]biphenyl-2carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 8% of theory, SOS' Melting point: 198-2001C
C
32
H
35
N
7 0 2 (549.70) Rf value: 0.30 (silica gel; eluant: methylene 9*f chloride/ethanol =9:1 by volume) Mass spectrum: (M 550 :Example 51 4' [2-n-Butyl-6- (2-oxo-pyrrolidin-l-yl) -benzi-midazol-lyl]-methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-butyl- 6- (2-oxo-pyrrolidin-1-yl) -benzimidazol-1-yl3methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 15% of theory, Melting point: 153-155*C I I I I
C
29
H
29 N 7 0 (491.60) Calculated: C 70.85 H 5.95 N 19.95 Found: 70.79 6.17 19.71 Rf value: 0.45 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) Mass spectrum: (M 492 Example 52 Mixture of 4' [2-n-butyl-6- l-dimethyl-2-hydroxy-ethylaminocarbonyl) -benzimidazol-l-yl] -methyl] yl)-biphenyl and 1-[[2-n-butyl-5- l-dimethyl-2-hydroxy-ethylaminocarbonyl) -benzimidazol-l-yl] -methyl] yl) -bipheny.
Prepared analogously to Example 41 from a mixture of 4I1 I [2-ri-hutyl-6- l-dimethyl-2-hydroxy-ethylaminocarbonyl) -benzimidazol-l-yl] -methyl]biphenyl-2carboxylic acid nitrile and 4 [2-n-butyl-5- (1,1dimethyl-2-hydroxy-ethylamino-carbonyl) -benzimidazol-1yl]-methyl]biphenyJ.-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 14% of theory, Melting point: amorphous
C
30
H
33 N 7 0 2 (523.60) Rf value: 0. 30 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) Mass spectrum: (M HI-) 524 -71 Example 53 4' [2-n-Butyl-6- (2-oxo-hexamethyleneimino) benzimidazol-l-yl] -methyl]-2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-buty1- 6- (2-oxo-hexamethyleneimino) -benzimidazol-l-yl] methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 34% of theory, Melting point: amorphous
C
31
H
33
N
7 0 (519.70) Calculated: C 71.65 H 6.40 N 18.87 *Found: 70.99 6.32 18.75 SRf value: 0.15 (silica gel; eluant: methylene S* f 0 chloride/ethanol 9:1 by volume) Example 54 4 '-1[2-n-Propyl-6-(2-oxo-piperidin-l-yl) -benzimidazol-lyl)-,methyl]-2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-n-propyl- 6- (2-oxo-piperidin-l-yl) enzirTnidazol-l-yl] methyl]biphenyl-2-carboxylic acid nitrile and sodium azide in dimethylformamide.
Yield: 14.5% of theory, S. Melting point: sintering from 125*C
C
29
H
29
N
7 0 (491.60) R Rf value: 0.25 (silica gel; eluant: methylene chloride/ethanol =9:1 by volume) Mass spectrum: (M 492 1 I I I 72 Example 4'-[[2-n-Butyl-6-(3,3-dimethylglutarimido)-benzimidazol- 1-yl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl a) 4'[[2-n-Butyl-6-(3,3-dimethylglutarimido)benzimidazol-1-yl]methyl]-2-(1-triphenylmethyl- 1.8 g (3.3 mMol) of 4'-bromomethyl-2-(l-triphenylmethylare added to a solution of 1.04 g (3.3 mMol) of 2-n-butyl-5-(3,3-dimethylglutarimido)-benzimidazole and 425 mg (3.8 mMol) of potassium tert.-butoxide in 25 ml of dimethylsulphoxide.
The mixture is stirred for 3 hours at ambient temperature, then stirred into 150 ml of water, extracted three times with 30 ml of ethyl acetate, then the organic extracts are dried and concentrated by evaporation. The residue obtained is purified by column chromatography (300 g of silica gel; eluant: ethyl acetate/petroleum ether (2:1 by volume)).
Yield: 400 mg (15% of theory), Rf value: 0.38 (ethyl acetate/petroleum ether 6:1) b) 4'-[[2-n-Butyl-6-(3,3-dimethylglutarimido)biphenyl A solution of 400 mg (0.5 mMol) of 4'-[[2-n-butyl-6- (3,3-dimethylglutarimido)-benzimidazol-l-yl] -methyl]-2in 10 ml of methanol is mixed with 1.5 ml of methanolic hydrochloric acid and stirred for 2 hours at ambient temperature, then concentrated by evaporation, the residue is mixed with 15 ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidification with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (150 g of silica gel; eluant: methylene 73 zhloride 5% ethanol).
Yield: 150 mg (55% of theory), Melting point: 184-186*C
C
32
H
33
N
7 0 2 (547.70) Calculated: C 70.18 H 6.07 N 17.90 Found: 69.98 6.20 17.67 Example 56 4'-[[2-n-Butyl-6-(N-methylaminocarbonyl-n-pentylamino)- Prepared analogously to Example 55 from 4'-[[2-n-butyl- 6-(N-methylaminocarbonyl-n-pentylamino)-benzimidazol-l- *i yl]methyl]-2-(l-triphenylmethyl-tetrazol-S-yl) -biphenyl and hydrochloric acid in ethanol.
Yield: 53.8% of theory, Melting point: 124-126*C
C
3 3
H
38
N
8 0 (550.71) Rf value: 0.25 (silica gel; eluant: methylene chloride/ethanol 9:1 by volume) goat** Calculated: C 69.79 H 6.95 N 20.35 Found: 69.78 7.05 20.31 Mass spectrum: (M 492 Example 57 dihydrate Prepared analogously to Example 55 from 4'-[[2-n-butyl- (N-metwivlaminocarbonyl-n-pentylamino) -benzimidazol-1yl and hydrochloric acid in ethanol.
Yield: 76.2% of theory, Melting point: 201-203 0
C
C
32
H
3 x 2 H 2 0 (586.74) 74- Calculated: C 65.50 H 7.21 N 19.09 Found: 65.43 7.07 19.12 ExaMple 58 [[2-n-Butyl-6- (N-cyclohexylaminocarbonyl-npentylamino) -benzimidazol1-yl~methy13-2-(lH-tetrazol-5yl) -biphenyl-hydrate Prepared analogously to Example 55 from 4'-[[2-'n-butyl- 6- (N-cyclohexylarinocarbonyl-n-pentylamino) benzimidazol-l-yl ]methyl] (1-triphenylmethyl-tetrazoland hydrochlo'ric acid in ethanol.
a O&WYield: 95.2% of theory, Melting point: 128-132'C 37 46
N
8 0 xHO0 (636.84) Calculated: C 69.78 H 7.59 N 17.59 4. ~Found: 69.61 7.71 17.41 Rf value: 0. 45 (silica gel; eluant: etha'nol/ammonia 80:40:2 by volume) Example 59 [[2-n-Butyl-5- (N-cyclohexylaminocarbonyl-npentylamino) yl) -biphenyl-hydrate Prepared analogously to Example 55 from 41-[[2-n-butyl- U 5-(N-cyclohexylaminocarbonyl-n-pentylamino) benzimidazol-l-yl~methyl]-2- (1-triphenylmethyl-tetrazoland hydrochloric acid in ethanol.
Yield: 88.6% of theory, Melting point: 117-120'C
C
37
H
4 ,N.0 x H 2 0 (636.84) Calculated: C 69.78 H 7.59 N 17.59 Found: 70.06 7.58 17.56 Rf value: 0.45 (silica gel; eluant: ethanol/ammonia 80:40:2 by volume) I I I 75 Example 4'-[[2-n-Butyl-6-(5-dimethylaminonaphthalen-lsulphonamino)-benzimidazol-l-yl]methyl]-2-(iH-tetrazol- Prepared analogously to Example 55 from 4'-[[2-n-butylbenzimidazol-l-yl]methyl]-2-(1-triphenylmethyl-tetrazoland hydrochloric acid in ethanol.
Yield: 44.7% of theory,
C
37
H
36
N
8 0 2 S x H 2 0 (674.81) Calculated: C 65.85 H 5.67 N 16.60 S 4.75 Found: 65.80 5.46 16.42 4.90 we Example 61
S
4' [2-n-Butyl-6-(2-oxo-3,4-tetramethylene-pyrrolidin-lyl)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 420 mg (0.81 mMol) of 4'-[[2-n-butyl-6-(2-oxo-l,2dihydro-3,4-tetramethylene-pyrrol-l-yl)-benzimidazol-lyl]methyl]biphenyl-2-carboxylic acid are dissolved in 60 ml of methanol and 60 ml of ethyl acetate and hydrogenated with the addition of 200 mg of palladium on *b charcoal under 5 bar of hydrogen pressure and at T;-n catalyst is removed by suction filtering, the solvent is evaporated off and the crude product is S* purified by column chromatography (200 g of silica gel; Sd 0 a *e eluant: methylene chloride 3% ethanol).
Yield: 260 mg (62% of theory), Melting point: amorphous
C
33
H
35
N
3 0 3 (521.67) Calculated: C 75.98 H 6.76 N 8.06 Found: 75.75 6.62 8.24 I I I I 76 Example 62 Mixture of 4 [2-n-butyl-6- 5-pentame-thylene-oxazolin-2-yl) benzimidazol-l-yl) methyl]-2- and 2-n-bultyl-5- 5-pentamethylene-oxazolin-2-yl) benzimidazol-l-yl) -methyl3-2- (lH-tetrazol-5-yl) -biphenyl A solution of 930 mg (2 mMol) of an isomer mixture of 4 -r [2-n-butyl-6-carboxy-benzimtdazol-l-yl] -methyl] -2- (lH-tetrazol-5-yl)--biphenyl and 4 carboxy-benzimidazol-l-yl]-methyl,]-2- (1H-tetrazol-5-yl) *biphenyl and 356 mg (2.2 mMol) of carbonyldiimoidazole in ml of tetrahydrofuran is stirred for 30 minutles at ambient temperature. Then 332 mg (2 niMol) of I- (aminomethyl) -cyclohexanol-dihydrochloride are added and the mixture is stirred for a further 15 hours at ambient temperature. The mixture is then concentrated by evaporation, 2 ml of thionyl chloride are slowly added dropwise, the m'ixture is stirred for one hour, the thionyl chloride is distilled of f and the residue is mixed with 5 ml of ice water. The insoluble crude product is purified by column chromatography (150 g of silica gel; eluant: methylene chloride 5% ethanol).
In this way, 25 mg of theor-y) of a mixture of 4'- S [2-n-butyl-6-(5,5--pentamethylene-oxazolin-2-yl)- *.:benzimidazol-l-yl3-methyl]-2-(lH-tetrazol-5-yl)-biphenyl and 4 2-n-butyl-5-(5,5-pentamethylene-oxazolin-2-yl) benzimidazol-l-yl] -methyl] (lH-tetrazol-5-yl) -biphenyI is obtained.
Melting point:k from 215'C (decomp.) 0 33
H
35
N
7 0 (545.67) Mass spectrum: (M =:46 77 Example 63 4'-[[2-n-Butyl-6-(N-methyl-phenylaminocarbonylamino)benzimidazol-1-yl]-methyl)biphenyl-2-carboxylic acid A solution of 0.8 g (2.00 mMol) of 4'-[[2-n-butyl-6aminobenzimidazol-l-yl]-methyl]biphenyl-2-carboxylic acid and 0.9 g of N-methyl-isatoic acid anhydride in 3 ml of pyridine is refluxed for 48 hours, then evaporated to dryness, the residue is suspended in about ml of methylene chloride, suction filtered, washed I. with a further 5 ml of methylene chloride and dried.
Yield: 0.66 g (62% of theory), Melting point: 274-276 C
C
33
H
3
N
4 0 3 (532.60) Calc lated: C 74.41 H 6.06 N 10.57 Found: 74.23 5.94 10.66 Example 64 S 4' 2-n-Butyl-5-(3-carboxy-propionyl)-benzimidazol-lyl]-methyl]biphenyl-2-carboxylic acid A solution of 200 mg (0.39 mMol) of methyl butyl-5-(3-methoxycarbonyl-propionyl)-benzimidazol-1yl]-methyl]biphenyl-2-carboxylate and 0.75 ml of sodium hydroxide solution in 4 ml of ethanol is stirred for 2 hours at 75°C, then mixed with 40 ml of water and acidified with glacial acetic acid. The alcohol is then distilled off, the resulting mixture is stirred for one hour at ambient temperature, the product precipitated is suction filtered, washed with 10 ml of water and dried.
Yield: 120 mg (64% of theory), Melting point: 200-202°C
C
29
H
28
N
2 0 4 (484.60) Calculated: C 71.88 H 5.83 N 5.78 Found: 71.66 5.86 5.63 I I -73 Example 4 '-[[2-n-Butyl-6- (3-carboxy-2-methyl-propionyl) benzimidazol-l-yl]methyl~biphenyl-2-carboxylic acid x 0.25 112 0 Prepared analogously to Example 64 from methyl butyl-6- (3-methoxycarbonyl-2-methyl-propionyl) benzimidazol-l-yl Imethyl ]biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 18% of theory, Melting point: 193-194*C
**C
3 0 11 30
N
2 0 5 x 1/4 H120 (498.60) Calculated: C 71.62 H 6.11 N 5.56 Found: 71.72 6.09 5.68 .5Rf value: 0.37 (silica gel; eluant: methylene chloride/ethanol/glacial acetic acid =18:1:0.05 by volume) go's soExample 66 a 0 4 f2-n-Butyl-6-(3-carboxy-prop4onyl)-benzimidazol-lyl ]methyl ]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl I butyl-6- (3-methoxycarbonyl-propionyl) -benzimidazol-lyl]methyl Ibiphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 97% of theorcy, Melting point: 240-242*C
C
29
H
28
N
2 0 5 (484.60) Calculated: C 71.88 H 5.83 N 5.78 Found: 71.74 6.07 5.93 I I I I 79 Example 67 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid 52.5 mg (0.1 mMol) of 4'-[[2-n-butyl-6-(2,3dimethylmaleic acid amino)-benzimidazol-l-yl]-methyl]biphenyl-2-carboxylate are heated to boiling for one hour in 2 ml of bis-(2-methoxy-ethyl)-ether. The solvent is removed by distillation and the oily residue is distributed in ethyl acetate/water. The organic phase is washed twice more with water, dried with magnesium sulphate and concentrated by rotary evaporation. The residue is triturated in 1 ml of acetone, suction filtered, washed with ether and dried i**n vacuo at Yield: 29.0 mg (57.2% of theory), Melting point: 289-291"C
C
31
H
29 N304 (507.59) Calculated: C 73.35 H 5.76 N 8.29 Found: 73.50 5.64 8.10 Example 68 4'-[[2-n-Butyl-6-(3,4,5,6-tetrahydro-phthalimino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acidhydrate 0.275 g (0.5 mMol) of 4'-[[2-n-butyl-6-(2-carboxy- 3,4,5,6-tetrahydrobenzamino)-benzimidazol-l-yl]methyl]biphenyl-2-carboxylate are refluxed for 4 hours in 5 ml of pyridine. The mixture is evaporated to dryness in vacuo by rotary evaporation and the crude product is recrystallised from acetone. It is suction filtered, washed with acetone and dried in vacuo at Yield: 0.2 g (72.4% of theory), Melting point: 226-228*C I I r i 80
C
30
H
31
N
3 0 4 x H 2 0 (551.64) Calculated: C 71.85 H 6.03 N 7.62 Found: 71.83 5.90 7.61 Example 69 Tert.-butyl 4'-[[2-n-butyl-6-(pyrrolidinocarbonylamino)benzimidazol-l-yl]methyl]biphenyl-2-carboxylate g (15 mMol) of pyrrolidinocarbonyl chloride are placed in 50 ml of dry chloroform and 2.3 g (6 mMol) of tert.-butyl 4'-[(6-amino-2-n-butyl-benzimidazol-1-yl)methyl]biphenyl-2-carboxylate dissolved in 50 ml of dry pyridine are added dropwise for one hour. The reaction solution is stirred for a further 24 hours and then concentrated by rotary evaporation. The oily residue is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution, the organic phase is separated off and, after drying with magnesium sulphate, concentrated by rotary evaporation. Purification is carried out using a silica gel column (particle .i e: 0.063 0.2 mr,, eluting with petroleum ether/ethyl acetate Th:. corresponding column fractions are concentrated by rotary evaporation and dried in vacuo at 0
C.
Yield: 1.7 g (61.8% of theory), Melting point: 68-70*C (amorphous)
C
34
H
40
N
4 0 3 (552.72) Rf value: 0.35 (silica gel; eluant: ethyl acetate/ethanol 19:1 by volume) Example 4'-[[2-n-Butyl-6-(pyrrolidinocarbonylamino)benzimidazol-L-yl]methyl]biphenyl-2-carboxylic acid trifluoroacetate-monohydrate Prepared analogously to Example 1 from tert.-butyl 4'- Si r I o -81- [[2-n-butyl-6-(pyrrolidinocarbonylamino)-benzimidazol-lyl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid/methylene chloride.
Yield: 91.7% of theory, Melting point: 233-234°C
C
30
H
32
N
4 0 3 x CF 3 COOH x H 2 0 (628.25) Calculated: C 61.14 H 5.61 N 8.91 Found: 61.25 5.62 9.09 Rf value: 0.48 (silica gel; eluant: ethyl acetate:ethanol:ammonia 50:45:5 by volume) s Example 71 e* 4'-[[2-n-Butyl-6-(2,3-dimethylmaleic acid imino)ago* benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 314 mg (0.5 mMol) of 4'-[(6-amino-2-n-butylbenzimidazol-l-yl)-methyl]biphenyl-2-carboxylic acid trifluoroacetate are refluxed together with 76 mg (0.6 mMol) of 2,3-dimethylmaleic acid anhydride in 10 ml of pyridine for 18 hours. The solvent is then removed by rotary evaporation and the oily substance is distributed in ethyl acetate and 10% sodium hydrogen carbonate solution. The organic phase is separated off, dried with magnesium sulphate and concentrated by rotary evaporation after being filtered. By trituration with acetone and ether, a white crystalline product is obtained which is dried at 50*C in vacuo after suction filtering.
Yield: 165 mg (65.0% of theory), Melting point: 288-290*C
C
31
H
29
N
3 0 4 (507.59) Calculated: C 73.35 H 5.76 N 8.29 Found: 73.14 5.94 8.32 I I I I -82- Example 72 [(2-n-Butyl-6-hexahydrohomophthalimino-benzimidazol- 1-yl) -methyllbiphenyl-2-carboxylic acid Prepared analogously to Example 71 from 4'-[(6-amino-2n-butyl-benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid and hexahydrohomophthalic acid anhydride in pyridine.
Yield: 15.3% of theory, Melting point: 183-185*C
:C
34
H
35
N
3 0 4 (549.67) Calculated: C 74.29 H 6.49 N 7.64 .Found: 74.09 6.47 7.80 Example 73 4' [2-n-Butyl-6- (benzofuran-2-carbonylamino) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 71 from 4'-[(6-amino-2- 0o n-butyl-benzimidazol-l-yl) -methyl.]biphenyl-2-carboxylic acid and benzofuran-2-carboxylic acid anhydride in pyridine.
Yield: 80.7% of theory, :000 Melting point: 321-323'C
:C
34
H
39
N
3 0 4 (543.62) Calculated: C 75.12 H 5.38 N 7.73 Found, 74.92 5.45 7.87 Example 74 4 [2-n-Butyl--6-(3-benzyl.-3,4 6-tetrahydro-2 (lH) pyrimidinon-l-yl) -benzimidazol-l-yljmethyl]biphenyl-2carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6-(3-benzyl-3,4,5, 6-tetrahy-dro-2 (lH)pyrimidinon-l-yl) -benzimidazol-1-yl]-metthyl]biphenyll-2carboxylate and trifluoroacetic acid in methylene I I T I -83 chloride.
Yield: 42.2% of theory, Melting point: 119-122*C
C
36
H
36
N
4 0 3 X H 2 0 (590.72) Calculated: C 73.20 H 6.48 N 9.48 Found: 73.11 6.50 9.67 Example [[2-n-Butyl-6- (2-carboxy-cyclohexylmethylcarbonylamino) -benzimidazol-l-yl]methyl]biphenyl-2-carb Dxylic acid hydrate a) Tert.-butyl 4 [2-n-biutyl-6-(2-carboxycyclohexylinethylcarbonylamino) -benzimidazol-l-yl3 methyll1biphenvl-2--carbcxylate 1.3 g (2.86 mMol) of tert-,.-butyl 4'-[(6-amino-2-n-butylbenzimidazol-1-yl) -methyl]biphenyl-2-carboxylate, 0.6 g (5.35 inMol) of hexahydrohomophthalic acid anhydride and ml of pyridine are ref luxed with stirring for 3 hours.
Then the pyridine is removed by rotary evaporation in vacuo, the residue is crystallised from acetone, washed with acetone and dried in vacua at Yield: 0.67 g (37.6% of theory), :0,0 Melting point: 227-229*C
C
38
H
45
N
3 0 5 (623.79) Calculated: C 73.17 H 7.27 N 6.74 Found: 72.93 7.15 6.94 b) [[2-n-butyl-6- (2-carboxy-cyclohexylmethylcarbonylamino) -benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 0.6 g (0.06 mMol) of tert.-butyl 4'-([2-n-butyl-6-(2carbox--y-cyclohexylmethylcarbonylaminQ) -benzimidazol-1yl]mpethyl]biphenyl-2-carboxylate, 30 ml of methylene chloride and 10 ml of trifluoroacetic acid are stirred for 3 hours at ambient temperature. The mixture is diluted with 20 ml of methylene chloride, extracted with I I I I 84 water, the organic phase is dried over sodium sulphate and evaporated to dryness. The residue is dissolved in ethanol and made alkaline by the addition of ammonia.
The solvent is distilled off in vacuo. The remaining aqueous solution is acidified with acetic acid, the product which crystallises out is suction filtered, washed with water and dried in vacuo at Yield: 0.55 g (98.2% of theory), Melting point: 160-162°C
C
34
H
37
N
3 0 5 x H 2 0 (585.68) Calculated: C 69.72 H 6.71 N 7.17 Found: 69.63 6.64 7.33 *3 Example 76 4'-[[2-n-Butyl-6-(2-carboxy-3,4,5,6-tetrahydrobenzamino)-benzimidazol-l-yl]methyl]biphenyl-2carboxylic acid 0.4 g (1 mMol) of 4'-[(6-amino-2-n-butyl-benzimidazol-lyl)-methyl]biphenyl-2-carboxylic acid, dissolved in 7 ml of pyridine, are mixed with 0.34 g (1.1 mMol) of 1cyclohexene-l,2-dicarboxylic acid anhydride at ambient temperature and stirred for 2h hours. The mixture is cooled with ice and the product which crystallises out is suction filtered, washed with cooled acetone and dried in vacuo at Yield: 0.37 g (67.2% of theory), Melting point: 250-252°C
C
33
H
33
N
3 0 5 (551.64) Calculated: C 71.85 H 6.03 N 7.62 Found: 71.70 5.99 7.60 r I r I 85 Example 77 4'-[[2-n-Propyl-6-(l-methylbenzimidazol-2-yl)benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 604 mg (1.0 mMol) of tert.-butyl 4'-[[2-nitro-5-(1methylbenzimidazol-2-yl)-N-n-butyryl-anilino]methyl]biphenyl-2-carboxylate are stirred in 50 ml of methylene chlorida with the addition of 10 ml of trifluoroacetic acid at ambient temperature for 3 hours. The solvent is then distilled off, the residue is dissolved in 25 ml of glacial acetic acid and hydrogenated at 80"C with the addition of 500 mg of 10% palladium/charcoal. In order to work up the product, the solvent is distilled off in vacuo, the residue is dissolved in 30 ml of 2N sodium hydroxide solvtion and the solution is washed with 20 ml of diethyl ether. The crude product precipitated by the acidification of the aqueous phase is purified by subsequent column chromatography (80 g silica gel, eluant: methylene chloride/methanol 15:1 by volume).
Yield: 90 mg (18% of theory), Melting point: 214-216°C
C
32
H
28
N
4 0 2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.58 5.49 11.30 .s*o Example 78 4'-[[2-n-Propyl-6-(l-methylbenzimidazol-2-yl)benzjinidazol-l-yl]methyl]biphenyl-2-carboxylic acid A suspension of 940 mg (2.0 mMol) of tert.-butyl n-propyl-6-carboxy-bentimidazol-l-yl)-methyl]biphenyl-2carboxylate and 320 mg (2.0 mMol) of carbonyldiimidazole in a solution of 1.0 ml of triethylamine in 30 ml of tetrahydrofuran is stirred for 30 minutes at ambient temperature, then 250 mg (2.0 mMol) of 2-methylaminoaniline are added and the mixture is stirred for a I I I 0 86 further 16 hours. It is then evaporated to dryness and the residue is refluxed in 20 ml of phosphorus oxychloride, with stirring, for 1 hour. The majority of the phosphorus oxychloride is then distilled off, the dark, greasy residue is decomposed with 30 ml of water, the strongly acidic suspension thus obtained is refluxed for about 1 hour, adjusted to pH 6 after cooling and then concentrated by evaporation. The crude product obtained is purified by column chromatography (120 g of silica gel, eluant: methylene chloride/methanol 15:1 by volume).
Yield: 73 mg of theory), S Melting point: 213-215°C
SC
32
H
28
N
4 0 2 (500.60) Calculated: C 76.78 H 5.64 N 11.19 Found: 76.61 5.64 10.94 Example 79 4'-[[2-n-Propyl-6-(2-oxo-piperidin-l-yl)-benzimidazol-l- Within 10 minutes, 155 mg (1.0 mMol) of acid chloride, dissolved in 5 ml of tetrahydrofuran, are added dropwise to a solution of 650 mg (1.0 mMol) of 4'- (2-n-propyl-6-amino-benzimidazol-l-yl)-methyl]-2-
(H-
triphenylmethyl-tetrazol-5-yl)-biphenyl in 30 ml of tetrahydrofuran and the mixture is stirred for a further hour at ambient temperature, then evaporated to dryness.
The residue is stirred into 20 ml of ethanol, then a solution of 2.0 mMol of sodium ethoxide in 20 ml of ethanol is added and the resulting mixture is refluxed for one hour. After cooling, 10 ml of methanolic hydrochloric acid are added dropwise, the mixture is stirred for a further two hours at ambient temperature and then evaporated down. The residue is mixed with ml of water and made alkaline with concentrated ammonia, whereupon the product goes into solution. By acidifying with glacial acetic acid the crude product is Ij I -87precipitated and then purified by column chromatography g silica gel, eluant: methylene chloride ethanol).
Yield: 54 mg (11% of theory), Melting point: sintering from 117*C
C
29
H
29
N
7 0 (491.60) Calculated: C 70.85 H 5.95 N 19.95 Found: 70.69 5.94 19.99 The following compounds are obtained analogously: 4 [2-n--butyl-G- (2-oxo-piperidin-l-yl) -benzimidazol-l- S. yl ]methyl] (lH-tetrazol-5-yl) -biphenyl Yield: 16% of theory, Melting point: amorphous
C
30
H
31
N'
7 0 (505.63) Calculated: C 67.94 H 6.23 N 17.33 Found: 67.81 6.29 17.18 [2-n-butyl-6-(2-oxo-pyrrolidin-l-yl)-benzimidazol-lyl]methyl] (lH-tetrazol-5-yl) -biphenyl Yield: 9% of theory, Melting point: 150-151*C
C
29 H 29
N
7 0 (491.60) Calculated: C 70.85 H 5.95 N 19.95 :.*Found: 70.61 6.08 19.80 Example 4' [2-n-Butyl-6- (propanesultam-l-yl) -benzimidazol-lyl] -methyl] (lH-tetrazol-5-yl) -biphenyl Within 10 minutes, a solution of 265 mg (1.5 mMol) of 3chloro-propanesulphonic aci~d chloride in 5 ml of tetrahydrofuran is added dropwise to a solut'-on of 665 mg (1.0 mMol) of 4'-[(2-n-butyl-6-aminobenzimidazoll-yl) -methyl] (l-triphenylmethyl-tetrazol-5-yl) bipheny1 and 1 ml of triethylamine in 30 ml of tetrahydrofuran and the mixture is stirred for 1 hours 1 I I I 88 at ambient temperature. The mixture is then evaporated to dryness, the residue is taken up in 20 ml of ethanol, a solution of 3.0 mMol of sodium ethoxide in 20 ml of ethanol is added and the resulting mixture is refluxed for two hours. After cooling, 10 ml of methanolic hydrochloric acid are added dropwise, the mixture is stirred for a further two hours at ambient temperature and finally concentrated by evaporation. The residue is mixed with 10 ml of water and brought into solution with concentrated ammonia. By acidifying with glacial acetic acid, the crude product is precipitated and then purified by column chromatography (70 g of silica gel, eluant: methylene chloride 5% ethanol).
Yield: 68.5 mg (13% of theory), *Melting point: 202-205°C S.o. C 28
H
29
N
7 0 2 S (527.70) Calculated: C 63.73 H 5.54 N 18.58 Found: 63.70 5.61 18.35 The following compounds are obtained analogously:
S
4'-[[2-n-butyl-6-(butanesultam-1-yl)-benzimidazol-lyl]methyl]-2-(1H-tetrazol-5-yl)-biphenyl Yield: 10% of theory, Melting point: 185-187°C
C
29
H
31
N
7 0 2 S (541.70) Calculated: C 64.30 H 5.95 N 18.10 Found: 64.19 5.91 17.92 4'-[[2-n-propyl-6-(butanesultam-l-yl)-benzimidazol-l- -biphenyl Yield: 17% of theory, Melting point: 203-205°C
C
28
H
29
N
7 0 2 S (527.63) Calculated: C 63.73 H 5.54 N 18.58 Found: 63.63 5.54 18.39 I j fI -89 Examp]e_81 4' -r[2-n-Butyl-6-(l-benzyl-imidazolidin-2 ,4-dion-3-yl) benzimidazol-l-yl ]methyl Jbiphenyl-2-carboxylic acid trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6--(1-benzyl-imidazolidin-2,4-dion-3-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 58% of theory, sob Melting point: amorphous
:C
35
H
32
N
4 0 4 X CF 3 000H (686.71) 0*:Calculated: C 64.72 H 4.84 N 8.16 F ound: 64.48 4.68 8.09 I~*Example 82 4 2-n-Propyl-6-(5,5-pentamnethylene-imidazolidin-2, 4dion-3-yl) -benzimidazol-l-yllmeth'l]biphenyl-2- 0 carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- 0 [[2-n-propyl-6-(5,5-pentamethylene-imidazolidin-2,4dion-3-yl) -benzimidazol-l-yl]methyljbiphenyl-2carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 27% of theory, Melting point: amorphous
C
33
H
34
N
4 0 4 (550. 63) Calculated: C 71.98 H 6.22 N 10.18 Found: 71.93 6.16 10.09 Rf value: 0. 60 (silica gel; eluant: iuethyl4,ne chloride/ethanol 9:1 b~y volume) I r I Example 83 4 [2-Ethyl-6- (2-oxo-piperidin-l-yl) -benzi-midazol-1 yl]-methyl]-2- Prepared analogously to Example 41 from 41-[[2-ethyl-6- (2-oxo-piperidin-l-yl) -benzimidazol-l-yl]methyl)biphenyl-2-carboxylic acid nitrile and sodium azide in dimethyl formamide.
Yield: 33% of theory, Melting point: sintering from 150 0
C
*C
28
H
27 N 7 0 (477.58) in* Calculated: C 70.42 H 5.70 N 20.53 O*Found: 70.48 5.72 19.88 Example 84 4' [2-Ethyl-6- (butanesultam-1-yl) -benzimidazol-lyl~metLhyl] (1H1-tetrazo1-5-yl) -biphenyl Prepared analogously to Example 41 from 41-[[2-ethyl-6- (butanesultam-1-yl) -benzimidazol-l-yl ]methyl] biphenyl-2carboxcylic acid nitrile and sodium azide in **.dimethylformamide.
Yield: 36% of theory, Melting point: ;onposition from 240 0
C
V,66S 0 0 C 27
H
27
N
7 0 2 S (513.64) Calculated: C 63.14 H 5.30 N 19.09 Found: 63.06 5.19 19.08 Example 4 '-[[2-n-Propyl-6-(3-n-hexyl-imidazo[4, 5-bjpyridin-2yl) -benzimidazol-1-yl~methyl]biphenyl-2-carboxylic acid Prepared analogously to~ Example 1 from tert.-butyl 4'- [[2-n-propyl-6- (3-n-hexyl-imidazof4,5-b]pyridin-2-yl) benzimidazol-1-yl Jmethyljbiphenyl-2-carboxylate and I I I I '91 trif luoroacetic acid in nethylene chloride.
Yield: 57% of theory, Melting point: amorphous
C
36
H
37
N
5 0 2 (571.74) Calculated: C 75.63 H 6.52 N 12.25 Found: 75.58 6.48 12.08 Example 8'6 4 2-n-Propyl-6- (3-xnethyl-imidazo[(4, 5-b)pyridin-2-yl) 0S benzimnidazol-l-yl]methyl]biphenyl-2-carboxylic acid U. Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6-(3-methyl-iinidazo[4,5-b]pyridin-2-yl) *$floe; .6 benzimidazol-1-yl 3methyllbiphenyl-2-carboxylate and trifluoroacetic acid in miethylene chloride.
Yield: 40% of theory, Melting point: 208-210*C b C 31 H 27
N
5 0 2 (901.60) a:....Calculated: C 74.23 H 5.43 N 13.96 ~eFound: 74.1.9 5.32 13.94 Example 87 4 [2-n-Propyl-6-(l-methyl-imidazolin-2-yl) b C benzimidazol-l-yl]methylbiphenyl-2-carboxylic acid Prepared analogously to Example 1 f rom tert. -butyl 4'- [2-n-propyl-6- (l-methyl-imidazolin-2-yl) -benzinddazol- 1l-yl ]methyl ]biphenyl -2 -carboxyl ate and trifluoruacetic acid in methylene chloride.
Yield: 53% of theory, Melting point: amorphous C 28
H
28 N 4 0 2 (452.57) Calculated: C 74.31 H 6.24 N 12.38 Found: 74.31 6.11 12.27 r I -92 The following compounds are obtained analogously to Example 87: 4 [2-n-butyl-6-(1-methyl-imidazolin-2-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid 4 r2-n-propyl-6-1I-n-hexyl-imidazolin-2-yl) benzimidazol-l-yi3methyl]bipheiyl-2--carboxylic acidl 4 2-r-butyl-6- (l-n-butyl-imidazolin-2-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid [2-n-propyl-6-(l-cyclopropyl-imidazolin-2-yl) 0* benzimidazol-l-yljmethyl]biphenyl-2-carboxylic acid 4 [2-n-propyi-6-(1-cclhexl-imidazoli-l-yl benzimidazol-1-yljmethyl]biphienyl-2-carboxylic acid 4 [2-n-propyl-6-(l-n-etyl-imidazol-2.-yl)-benzimidazoll-yl~methyl]biphenyl-2-carboxylic acid 4 [[2-n-butyl-6-(l-ethyl-imidazol-y)-benzmidzol beziilo--yl]methyl]biphenyl-2-carboxylic acid -93- Example 88 4 2-n-Propyl-6- 5-dimethyl-benzimidazol-2-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6- 5-dimethyl-benzimidazol-2-yl) benzimic2azol-l-yl]methy1]biphenyl-2-carboxylate and trifluoroacet', acid in methylene chloride.
Yield: 48% of theory, Melting point: 256-258'C *.0:C 3 3
H
30
N
4 0 2 (514.63) Calculated: C 77.02 H 5.88 N 10.89 *Found: 76.91 5.83 10.72 ****Example 89 4 [2-n-Propyl-6- benzimidazol-2-yl) -benzimidazol-1-yl]methyl]biphenyl-2seso carboxylic acid Prepared analogously to Example 1 from tert.-buty. 4'- [[2-n-propyl-6- 2 -yl) -benz imidazoL-l-yl ]methyl] biphenyl-2 -carboxylate and trifluoroacetic acid in inethylene chloride.
Yield: 56% of theory, :Melting point: 183-186*C
C
33
H
27 F 3 N 4 0 2 (568.61) Calculated: C 69.71 H 4.79 N 9.85 Found: 69.58 4.72 9.80 I I 1 1, -94- Example 4' [2-n-Propyl-6- (5-methyl-im.idazolidin-2, 4-dion-3-yl) benzimidazol-l-yl~methyl]biphienyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-propyl-6-(5-miethyl-imidazolidin-2,4-dion-3-yl) benzimidazol-l-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 29% of theory, Melting point: amorphous H~ CH 2 No0 (482.55) Calculated: C 69.69 H 5.43 N 11.61 *Found: 69.67 5.40 11.55 0*oo: a So .1 4,*o Exanv~e 91 4- (2-n-Propyl-6- (1-methyl-imidazolidin-2, 4-dion-3 -yl) benzimidazol-1-yl) -methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- (2-n-propyl-6- (l-methyl-imidazolidin-2,4-dion-3-yl) benz imida zol -l-yl) -methyl biphenyl-2 -carboxyl ate and 00 trifluorcacetic acid in methylene chloride.
Yield: 32% of theory, VtootMelting point: amorphous 0. S S. *C 2
B
2 N0 (482.55) Calculated: C 69.69 H 5.43 N1 11.61 Found: 69.61 5.38 11.49 Example 92 4 (2-n-Propyl-6-(l-butyl-benzimidazol-2-y1) benzimidazol-l-yl) -methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- (2-n-propyl-6- (1-butyl-benzimidazol-2-yl) -benzimidazoll-yl) -methyl ]biphenyl-2-carboxylate and trifluoroacetic It acid in methylene chloride.
Yield: 59% of theory, Melting point: sintering from 149*C
C
3 5
H
34
N
4 0 2 (542.69) Calculated: C 77.46 H 6.32 N 10.32 Found: 77.37 6.31 10.35 Example 93 4'-1 (2-n-Butyl-6-(lH-benzimidazol-2-yl)-benzimidazol-lyl) methyl] biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [C(2-n-butyl-6- (1H-benzimidazol-2-yl) -benzimlidazol-l-yl) methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 62% of theory, Melting point: 200-202*C
C
32
H
28
N
4 0 2 (500.61) calculated: C 76.78 H 5.64 N 11.19 *Found: 76.54 5.60 11.16 ~**Example 94 [(2-n-Butyl-6-hexahydrohomophtlialimino-benzimidaz l- *1-yl',methyl~biphenyl-2-carboxylic acid 0.4 g (0.64 mMol) of tert.-butyl 4'-[(2-n-butyl-6-(2carboxy-cycl ohexylmethyl carbonyl amino) -benz imidazol-lyl)-methyl]biphenyl-2-carboxylate are ref luxed for 1k hours with stirring in 5 ml of phosphorus oxychioride.
After cooling, the mixture is poured onto ice water and the crude product precipitated is removed by suction filtering. This is dissolved in ethanol/water, made alkaline with ammonia and concentrated in vacuo until it crystallises out. It is then suction filtered, washed with water and dried in vacuo at 1200C.
Yield: 0.15 g (42.8% of theory), 1 1, 1 W4 *no U. 06 96 Melting point: 241-243*C
C
34
H
35
N
3 0 4 (549.66) Calculated: C 74.29 H 6.49 N 7.64 Found: 74.14 6.64 7.81 Example 4 (2-n-Butyl-6- (7-nitro-benzofurazan-4-yl-aminio) benzimidazol-l-yl) -methyl] biphenyl-2-carboxylic acid Prepared from 4 (6-amino-2-n-butyl-benzimidazol-lyl) methyl] biphenyl-2-carboxylic acid and 4-chloro-7nitro-benzofurazan in pyridine at ambient temperature.
Yield: 13.1% of theory, Rf value: C.75 (silica gel, methylene chloride/ethanol 9:1)
C
31
H
26
N
6 0 5 (562.58) Calculated: C 66,18 H 4.66 N 14.93 Found: 66.35 4.76 15.13 Example 96 4' 2-Ethyl- 6- (pyrrol id inocarbonyl amino) -benzimidazoll-yl ]methyl ]biphenyl-2-carboxylic acid-trifluoroacetatesemihydrate Prepared analogously to Example 2. from tert.-butyl 4'- [[2-ethyl-6- (pyrrolidinocarbonylamino) -benzimidazol-lyl] -methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 80.9% of theory, Melting point: 178-179*C
C
2 8
H
28
N
4 0 3 X CF 3 COOH x 0.5 H 2 0 (591.59) Calculated: C 60.90 H 5.11 N 9.47 Found: 61.10 5.22 9.26 Rf value: 0. 48 (silica gel; ethyl acetate/ethanol/ammonia 50:45:5 by volume) I I I I 97 Exampile 97 4 [2-Methyl-6- (pyrrolidinocarbonylamino) -benzimidazoll-yl~methyl ]biphenyl-2-carboxylic acid-trifluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-inethyl-6- (pyrrolidinocarbonylamino) -benzimidazol-1yl] -methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 82.1% of theory, Melting point: 181-182'C 27 H 26 N 4 0 3 x CF 3 COOH (568.55) go 0.
Calculated: C 61.26 H 4.79 N 9.85 Found: 60.99 5.09 9.89 Rf value: 0.38 (silica gel; ethyl acetate/ethanol/ammonia S 50:45:5 by volume) Example 98 [2-n-Propyl-6- (pyrrolidinocarbonylamino) benzimidazol-l-yljmethyl]biphenyl-2-carboxylic acidtri fluoroacetate 0 eg Prepared analogously to Example 1 from tert.-butyl 4'r [2-n-propyl-6- (pyrrolidinocarbonylamino) -benzimaidazoll-yl ]met hyl.]biphenyl-2-carboxylate and trifluoroacetic :acid in methylene chloride.
Yield: 79.7% of theory, Melting point: 207-208'C
C
29
H
30 N 4 0 3 X CF 3 COOH (596.61) Calculated: C 62.41 H 5.24 N 9.39 Found: 62.38 5.36 9.42 R f value: 0.55 (silica gel; ethyl acetate/ethanol/ammnonia 50:45:5 by volume) I I -98- Example 99 4' [2-Methylmnercapto-6- (pyrrolidinocarbonvlamino) benzimidazol-l-yl~methyl]biphenyl-2-carb-oxylic acidtri fluoroacetate Prepared analogously to Example 1 from tert.-butyl 4'- [2-methylmercapto-6- (pyrrolidinocarbonylamino) benzimidazol-l-yl]methyllbiphenyl-2-carboxylate and trufluoroacetic acid in methylene chloride.
Yield: 96.1% of theory, 0 age S. Melting point: 177-178'C
*C
27
H
26
N
4 0 3 S x CF 3 COOH (600.61) Calculated: C 57.99 H 4.53 N 9.33 s Found: 57.68 4.75 9.30 Rf value: 0.52 (silica gel; ethyl acetate/ ethanol/ ammon ia =50:45:5 by volume) Example 100 4' 6- 3-Dimethylmaleic acid imido) -2-methylmercaptobenzimidazol-l-yl]methyl]biphenyl-2-r, rboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- 3-dimethylmaleic acid imido) -2-methylmercaptobenzimidazol-l-yl~methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 91.7% of theory, Melting point: 276-.277*C
C
28
H
23
N
3 0 4 S (497 .57) Calculated: C 67.59 H 4.66 N 8.45 S 6.44 Found: 67.57 4.94 8.40 6.37 Rf value: 0.~47 (silica gel;e ethyl acetate/ethanol/ammonia 50:45:5 by volume) r I I -99 Example 101 4 [2-n-Butyl-6-[3-(7-nitrobenzofurazan-4-yl-amino) propionylamino]benzimidazol-1-yl)methyl] (11-tetrazol- -biphenyl-hydrate Prepared analogously to Example 55 from 4'-[[2-n-butyl- 6- (7-nitrobenzofurazan-4-yl-amino) -propionylamino] benzimidazol-1-yl ]methyl] (l-triphenyl:methyl-tetlrazoland 2 N hydrochloric acid in ethanol.
Yield: 33.3% of theory, Melting point: 179-181'C
C
34
H
31
N
11 0 4 x 1120 (675.70) Calculated: C 60.43 H 4.92 N 22.80 Found: 60.24 5.09 22.69 Example 102 4 [2-n-Butyl-6-[3- (7-nitrobenzofurazan-4-yl-amino) ea e 6 0 propionylamino]benzimidazol-l-yl]methyljbiphenyl-2- :14. carboxylic acid-trifluoroacetate-hydrate Prepared analogously to Example 1 from tert.-butyl 4'- [[2-n-butyl-6-[3- (7-nitrobenzofurazan-4-yl-aminio) propionylamino]benzimidazol-l-yl]methyl 3biphenyl-2carboxylate and trifluoroacetic acid in methylene :chloride.
Yield: 87.5% of theory, Melting point: 127*C (decomp.)
C
34
H
31
N
7 0 6 X CF 3 COOH x H120 (765.69) Calculated: C 56.47 H 4.47 N 12.80 Foundt 56.68 4.27 12.67 -100- Exam~le 103 4 [6-(2,3-Dimethylmaleic acid imido) -2-methylbenzimidazol-l-yl.]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- 3-dimethyl-inaleic acid imido) -2-methylbenzimidazol-l-yllmethyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 94.4% of theory, Melting point: 327-3281C too0 C 28
H
23
N
3 0 4 (465.51) :Calculated: C 72.25 H 4.98 N 9.03 Found: 72.00 5.08 9D.06 Rf value: 0.33 (silica gel; ethyl acetate/ethanol/ammonia =50:45:5 by volume) Example 104 e 4 [6-(2,3-Dimethyrln~aleic acid i-mido) -benzimidazol-lylTety ipe.:l aboyi acid-semihydrate Prepared analogously to Example 1 from tert.-butyl 4'vowC [[6-(2,3-dimethylmaleic acid imido) -benzimidazol-l-vi1methyl] biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: i5.5% of theory, Melting point: 223-2241C
C
27
H
21
N
3 0 4 X 0.5 H120 (460.49) Calculated: C 70.42 H 4.82 N 9.13 Found: 70.30 4.88 8.81 Rf value: 0. 34 (silica gel; ethyl acetate/ethanol/ainmonia =50:45:5 by volume) -101- Example 105 4 ,3-Dimethylmaleic acid imido) -2-n-propylbenzimidazol-l-yl methyl ~biphenyl-2-carboxylic acidmonohydrate Prepared analogously to Example 1 from tert.-butyl 4'- ,3-dimethylmaleic acid imido) -2-n-propylbenzimidazol-l-yl ]methyl ]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Go Yield: 92.5% of theory, :Melting point: 309-310*C
:C
3
,H
27
N
3 0 4 x H120 (511.58) *Calculated: C 70.44 H 5.71 N 8.21 Found: 70.44 5.64 8.19 0. f* value: 0. 47 (silica gel; ethyl a -etate/ ethanol/ ammon ia =50:45:5 by volume) Example 106 4 3-Dimethylmaleic acid imido) -2-ethylbenzimidazol-l-yl methiyl Ibiphernyl-2-carboxyl ic acid Prepared analogously to Example I from tert.-butyl 4'- [[6-(2,3-dimethylmaleic: acid imido)-2-ethylbenzimidazol-l-yrl]methvl]biphenyl-2-carboxylate and :trifluoroacetic acid in methyJ.,ene chloride.
Yield: 87.5% of theory, Melting point: 307-308*C
C
29
H
25
N
3 0 4 (4:19.53) Calculated: C 72.64 H- 5.25 N 8.76 Found: 72.41 5.37 8.94 Rfvalue: 0.40 (silica gel; ethyl acetate/ ethanolI/ ammon ia 50:45:5 by volume) j F 102 Example 107 4 [2-Ethyl-6-(l-methylbenzimidazol-2-yl) -benzimidazol- 1-yl]methyl ]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [[2-ethyl-6- (l-methyl-benzimidazol-2-yl) -benzimidazol-lyl]methyl]biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Yield: 31% of theory, Melting point: 183-185C s ee
C
31 H 26
N
4 0 2 (486.60) Calculated: C 76.52 H 5.39 N 11.52 *Found: 76.73 5,49 11.70 08 4 [2-Methyl-6- (butanesultam-l-yl) -benz iimidazol-lyl]methyl] (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 40-[[2-methyl-6- (butanesultam-l-yl) -benzimidazol-l-yl]methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.
0 seeYield: 27% of theory, Melting point: 173-175*C C 26 H 25
N
7 0 2 S (499.60) Calculated: C 62.51 H 5.04 N 19.63 S 6.42 *Found: 62.39 5.05 19.4.4 6.13 Mass spectrum: m/e 499 Example 109 4 [2-Methyl-6-(l-methylbenzimidazol-2-yl) benzimidazol-l-yl]methylJ-2- (lH-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 41-[[2-methyl-6- (1-methylbenzimidazol-2-yl) -henzimidazol-l-yl~methyl]-2cyano-biphenyl and sodium azide in dimethylformamide.
103 Yield: 26.5% of theory, Melting point: 214-217*C
C
30
H
24
N
8 (496.80) Calculated: C 72.56 H 4.87 N 22.56 Found: 72.32 5.01 22.23 Example 110 4 (Butarnesultam-1-yl) -benzimnidazol-l-yl]methyl]-2- (1H-tetrazol -5-yl) -biphenyl :4.:Prepared analogc'usly to Example 41 from (butanesultam-l-yl) -benzimidazol-l-yl]methyl] -2-cyanobiphenyl and sodium azide in dimethylformamide.
Yield: 60.0% of theory, ***Melting point: 246-2490C
C
25
H
23 N 7 0 2 S (485.60) Calculated: C 61.84 H 4.77 N 20.19 Found: 61.75 4.92 20.28 *Example- 111L 2- [-Ethyl -6 (-methylben z iidaz o1- 2-yl) -ben zimida zo 1l-yl methyl -2 (IH-tetra z c1- 5-yl) -b iphenyl :8,9 Prepared analogously to Example 41 from 4'-[[2-ethyl-6- (1 (nthyl -benz imida zol-2,-yl) -benz imidazol -l-yl ]methyl] *-yn-bpey and soimazide in dimethylformamide.
Yield: 41.0% of theory, Melting point: from 178'C (sintering)
C
31
H
26
N
8 (510.60) Calculated: C 72.92 H 5.13 N 21.95 Fo)und: 72.94 5.25 21.71 Mass spectrum: m/e 510 -104 Example 112 [[2-Ethyl-6- (N-benzenesulphonyl-inethylamino) benzimidazol-l-yl]methyl]-2- (1H-tetrazol-5-yl) -biphenyl Prepared analogously to Example 41 from 4'-[[2-ethyl-6- (N-benzenesulphonyl-methylamino) -benz imidazol-l-yl] methyl]-2-cyano-bipheriyl and sodium azide in dittethylformamide.
Yield: 66.0% of theory, Melting point: 226-228*C
C
30
H
2 NO0S (549.70) 30 27 7 Calculated: C 65.55 H 4.95 N 17.84 S 5.83 Found: 65.38 4.95 17.59 5.79 a Examp~le 113 4 [2-n-Propyl-6- (N-berenesulphonyl-methylamino) benzimiidazol-l-yl]methyl] (lI--tetrazol-5-yl) -biphenyl *:Prepared analogously to Example 41 from 4'-[[2-n-propyl- *se 6- (N-benzenesulphonyl-methylamino) -benzimidazol-l-yl 1methyl]-2-cyano-biphenyl and sodium azide in 0 diinethylforxnamide.
Yield: 83.4% of theory, Melting point: 177-179*C V66 C 31 H N 7 OS (563.70) Calculated: C 66.05 H 5.18 N 17.40 S 5.69 Found: 65.89 5.14 17.21 5.73 Example~ 114 4 (2-n-Butyl-6-benzenesulphonyloxy-benzimidazol-l-yl) methyl~biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [(2-n-butyl-6-benzenesulphonyloxy-benzimidazol-l-yl) methyl~biphenyl-2-carboxylate and trifluoroacetic aci.d in methylene chloride.
105 Yield: 8.2% of theory, Melting point: 193-195 0
C
C
31
H
2 &rI 2 5 S (540.60) Calculated: C 68.92 H 5.22 N 5.18 Found: 68.94 5.08 5.08 Example 115 4 r2-n-Butyl-6- (3-benzyl-3 6-tetrahydro-2 (1H1) pyrimidinon-l-yl) -benziiaidazol-l-yI] methyl] (lH- 00.
see tetrazol-5-yl) -biphenyl Prepared analogolisly to Example 55 from 4'-([2-n-butyl- 6- (3-benzyl-3 6-tetrahydro-2 (lH) -pyrimidinoi-1--yl) benzimidazol-l-yljmethyll (1-triphenylmethyl-tetrazol- 5-y2.) -bipheniyl and methanol in methanolic hydrochloric .ICIid~.
Yield: 28.0% of theory, Melting point: from 125 0 C (decomp.)
C
36
H
36
N
8 0 (596.80) 6 *Calculated: C 72.46 H 6.08 N 18.78 Found: 72.26 5.94 18.85 Example 116 .4 2[ [-n-Buty I- 5 -benzyl 4, 5, 6 -tetrahydro- 2 (1H) pyrimidinon-l-yl) -benzimidazol'-1-yl]-methyl]-2- (lH- -biphenyl Prepared analogously to Example 55 from 4'-[[2-n-butyl- (3 -ben zyJ.-3, 4, 5, 6 -tetrahydro-2 (lE) -pyrimidinon-l1-yl) benz imidazol-l1-yl ethyl (1-tri,_i enylmethyl -tetra zoland methanol in methanolic hydrochloric acid.
Yield: 31.0% of theory, Melting point: from 125*C (decomp.)
C
36
H
36 NB0 (596.80) Calculated: C 72.46 H 6.08 N 18.78 106- Found: 72.27' 6. 33 18.61 Example 117 4 '-[[2-n-Propyl-6-(3-benzyl-3,4 6-tetrahydro-2 (lH)pyrimidinon-1-yl) -benzimidazol-1-yl~methyl]-2- (lH- -biphenyl Prepared analogously to Example 55 frcai 4'-[[2-n-propyl- 6- (3-ben;zy1-3 14,5, 6-tetrahydro-2 (11) -pyrimidinon-1-yl) benzimidazol-1-yl]methyll (l-triphenylmethyl-tetrazol- 5-yl)-biphenyl and methanol in methanolic hydrochloric :acid.
Yield: 35.0% of theory, Melting point: from 132'C (decomp.)
C
3 5
H
3 4
N
8 O (582.71) Calculated: C 72.14 H 5.88 N 19.23 Found: 71.98 6.02 19.11 Example 118 050 4' 2-Ethyl- (3-benzyl-3 6-tetrahydro-2(1H) 0. pyrimidinon-1-yl) -benzimidazol-1-yl]methyll-2- (lHtetrazol-5-y1) -biphenyl e.Prepared analogously to Example 55 from 4'-[[2-ethyl-6- S. S (3-benzyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinon-1-yl) 0 00benzimidazol-1-yl]methyl] (1-triphenylmethyl-tetrazoland methanol in methanolic hydrochloric acid.
Yield: 22.0% of theory, Melting point: from 106*C (decomp.)
C
34
H
32 NB0 (568.68) Calculated: C 71.81 H 5.67 N 19.70 Found: 71.73 5.54 19.92 107 Example 119 [2-n-Butyl-6-(4, 5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-1-yl Imethyl ]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl butyl-6- 5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-l-yl~methyl] biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 80.0% of theory, Melting point: 276-283*C
*C
29
H
28
N
4 0 3 (480.60) Calculated: C 72.48 H 5.87 N 11.66 Found: 72.20 61 #*see*Mass spectrum: m/e 480 The following compounds are obtained analogously to Exam~ple 119: 4 [2-ethyl-6-.(2H-pyridazin-3-on-6-yl) -benzimidazol-lyl]methyl~biphenyl-2-carboxylic acid [2-n-propyl-6- (2H-pyridazin-3-on-6-yl) -benzimidazol- 61-yl 3methyl] biphenyl-2 -carboxyl ic acid :044004 [2-n-butyl-6-(2H-pyridazin-3-on-6-yl) -benzimidazol- 1-yl~methyl~biphenyl-2-carboxylic acid [2-n-propyl-6- (2bny-,5-dihydro-pyridazin-3-on- 6-yl) -benzimidazol-l-yl~methyl]biphenyl-2-carboxylic acid 0 -108- Example 120 4 [[2-n-Propyl-6- 5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-1i-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl propyl-6- 5-dihydro-2H-pyridazin-3-on-6-yl) benzimaidazol-1-yl] methyl] biphenyl-2-carboxylate and sodium hydroxide solution in ethanol.
Yield: 66.0% of theory, Melting point: 236-24l*C 0C 28
H
26
N
4 0 3 (466.54) Calculated: C 72.09 H 5.62 N 12.01 Found: 71.88 5.61 11.95 U. Example 121 4 [2-Ethyl-6-(4,5-dihydro-2H-pyridazin-3-on-6-yl) benzimidazol-l-yl]methyl]biphenyl-2-carboxylic acid Prepared analogously to Example 64 from methyl ethyl-6- 5-dihydro-2H-pyri~lazin-3-on-6-yl) benzimidazol-l-yljmethyl] biphenyl-2-carboxylate and 0 bwsodium hydroxide solution in ethanol.
Yield: 71.0% of theory, Melting point: 255-257*C
C
27 11 24
N
4 0 3 (452.51) :Calculated: C 71.67 H 5.35 N 12.38 Found: 71.41 5.51 12.12 Example 122 4 [2-n--Butyl-6- (3-cycl.ohexyl-propylamino) benzimidazol-l-yljmethyl]biphenyl-2-carboxylic acid Prepared analogously to Example 1 from tert.-butyl 4'- [2-n-butyl-6- (3-cyclohexyl-propylamino) -benzimidazol-lyl]mnethyl ]biphenyl-2-carboxylate and trifluoroacetic -109acid in methylene chloride.
Yield: 85.7% of theory, Melting point: 152-153*C
C
34 HjjN 3 0 2 X 0.75 CF 3 COOH (609.24) Calculated: C 69.99 H 6.91 N 6.90 Found: 70.02 6.93 6.84 Rf value: 0.24 (silica gel; ethyl acetate/ethanol/ammonia =80:40:2 by volume) 0 a 400 110 In the Examples of Pharmaceutical Formulations which follow, any suitable compound of formula I, particularly compounds A to L of the pharmacological test report, may be used as the active substance: Example I Ampoules containing 50 mg of active substance per 5 ml Active substance 50 mg *6
KH
2
PO
4 2 mg Na 2
HPO
4 x 2H 2 0 50 mg NaC1 12 mg Water for injections ad 5 ml Preparation: The buffer substances and isotonic substance are *dissolved in some of the water. The active substance is added and, once it has been completely dissolved, water is added to make up the required volume.
o** Example II Ampoules containing 100 mg of active substance per 5 ml Active substance 100 mg Methyl glucamine 35 mg Glycofurol 1000 mg Polyethyleneglycol-polypropyleneglycol block polymer 250 mg Water for injections ad 5 ml Preparation: Methyl glucamine is dissolved in some of the water and 111 the active substance is dissolved with stirring a\d heating. After the addition of solvents, water is added to make up the desired volume.
Example III Tablets containing 50 mg of active substance 0" e 0.
0 0 0 0 00 6
S
S@ 0 6
S
0* Active substance Calcium phosphate Lactose Corn starch Polyvinylpyrrolidone Magnesium stearate 50.0 mg 70.0 mg 40.0 mg 35.0 mg 3.5 mg 1.5 mq 200.0 mg Preparation: The active substance, CaHPO 4 lactose and corn starch are uniformly moistened with an aqueous PVP solution. The mass is passed through a 2 mm screen, dried at 50°C in a circulating air dryer and screened again.
After the lubricant has been added, the granules are compressed in a tablet making machine.
Example IV Coated tablets containing 50 mg of active substance Active substance Lysine Lactose Corn starch Gelatin Magnesium stearate 50.0 mg 25.0 mg 60.0 mg 34.0 mg 10.0 mg 1.0 m 180.0 mg 0 112 Preparation: The active substance is mixed with the excipients and moistened with an aqueous gelatin solution. After screening and drying, the granules are mixed with magnesium stearate and compressed to form tablet cores.
The cores thus produced are covered with a coating by known methods. A colouring may be added to the coating suspension or solution.
Example V Coated tablets containing 100 mg of active substance
C.
o0
C*
S. S
SS
S
9
S..
C
Active substance Lysine Lactose Corn starch Polyvinylpyrrolidone Microcrystalline cellulose Magnesium stearate 100.0 mg 50.0 mg 86.0 mg 50.0 mg 2..8 mg 60.0 mg 1.2 mq 350.0 mg *5 oS
S
C
5* a
C
o.
Preparation: The active substance is mixed with the excipients and moistened with an aqueous PVP solution. The moist mass is passed through a 1.5 mm screen and dried at After drying, it is screened again and the magnesium stearate is added. This mixture is then compressed into cores.
The cores thus produced are covered with a coating by known methods. Colourings may be added to the coating suspension or solution.
113 Example VI Capsules containing 250 mg of active substance Active substance Corn starch Magnesium stearate 250.0 mg 68.5 mg 1.5 mg 320.0 mg i.
*0
S
S.
S. S 0
S.
*c 0 Preparation: The active substance and corn starch are mixed together and moistened with water. The moist mass is screened and dried. The dry granules are screened and mixed with magnesium stearate. The final mixture is packed into size 1 hard gelatine capsules.
Example VII Oral suspension containing 50 mg of active substance per 5 ml S
*SSS
0 00 5 0 Active substance Hydroxyethylcellulose Sorbic acid 70% sorbitol Glycerol Flavouring Water ad 50.0 mg 50.0 mg 5.0 mg 600.0 mg 200.0 mg 15.0 mg 5.0 ml Preparation: Distilled water is heated to 70 0 C. Hydroxyethylcellulose is dissolved therein with stirring. By the addition of sorbitol solution and glycerol the mixture is cooled to ambient temperature. At ambient 114 temperature, sorbic acid, flavouring and active substance are added. The suspension is evacuated with stirring to remove any air. One drse of 50 mg is contained in 5.0 ml.
Example VIII Suppositories containing 100 mg of active substance Active substance Solid fat
S.
S.
*0* S. 0 0* *9 0S 0 0 0S
SSSSS@
S
S.
0
S.
100.0 mg 1600.0 mg 1700.0 mg Preparation: The hard fat is melted. At the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.
See...
S
OCS*
SO
S* S
S
0 0
Claims (4)
1. A compound of formula I (wherein R 1 represents a tetrahydrobenzimidazolyl or imidazo- pyrid 'nyl group, a benzimidazolyl or benzo~cazolyL group optionally sulbstituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a 3 -alkyl see group, by a C 1 3 -alkoxy or by a trifluoromethyl group, .1 0, 4:and in which the Nit-group of the above-mentioned imidazole rings may additionally be substituted by a C 1 6 -alkyl group or by a C 3 cycloalkyl group; an amino a group substituted by a bicyclohexylcarbonyl or biphenylcarbonyl group; or a hydroxy(C.--cycloalkyl)- aminocarbonyl group, which may additionally1. be a. 9. substituted at the N-atom by a C 1 3 -alkyl group; an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally also substituted by one or two C 1 3 -alkyl groups at the N-atom; a 6- or 7- asset: membered alky'leneimino or alkenyleneimino group optionally substituted by one ot two C 13 -alkyl groups or by a tetramethylene or pentamethylene group, in which a methylene group in the above mentioned alkylene and alkenylene moieties is replaced by a carbonyl or sulphonyl group; a 3,4,5, 6-tetrahydro-2 (lH-)-pyrimidinone group optionally substituted by a C 13 -alkyl or phenyl(C.. 3 '-alkyl) group; a straight-chained or branched hydroxy (C 4 6 -alkyl) amino-carbonyl group; a inaleic acid amido or maleic acid imido group opinlymn- or 116 disubstituted by a C 1 3 -alkyl. group or by a phenyl. group, in which the substituents may be identical or different; an imidazoline or imidazole c'roup optionally substituted by a C 1 -,-alkyl group or by a C 37 -cycloalkyl group; an imidazolidinedione group optionally substituted by a C 3 -alkcyl group, by a phenyl(C -,-alkyl) group or by a tetramethylene, pentamethylene or hexanmethylene group; a Cl- 6 -alkylsulphonyloxy group; a benzenesulphonyloxy group optionally substituted by a C. 3 ay.gopa alkylamino or phenyl(C 3 alkyl) amino group substituted by a C 4 6 -alkylsulphoriyi group or by a phenyl(C- 3 alkyl)sulphonyl group; an amino or C 1 3 alkylamino group ,substituted by a naphthalenesuilphonyl group optionally subetituted in the naphthalene ring by a di(Cl. 3 alkyl)- amino group or by one or two C 1 3 -alkoxy groups; a C 3 alkoxy group substituted in the 4- or 5-position by an imidazolyl group; a C 25 -alkoxy group substituted in 0' the 4- or 5-position by a benzimidazolyl or tetrahydro-benzimidazolyl group; a pyridazin-3-one or dihydro-pyridazin-3 -one group optionally substituted in the 2-position by an optionallyj phenyl-substituted Ci- 9 3 alkyl group and optionally additionally substituted at a carbon atom by 1 or 2 C 1 3 alkyl groups; a pyrrolidino, piperidino or hexainethyleneimino group substituted by two C 1 -3-alkyl groups; a 7-nitrobenzofurazan-4-yl- atnino(C 2 3 alkanoyl) amino group; a heptamethyleneimino, H,3H-uinazolin-2 ,4-diont-3-yl, pentamethylene-oxazolin-
2-yl, benzofuran-carbonylaminc. or 7-nitro-banzofurazan-
4-yl-anino group, and where R 3 represents a carboxy group and R2 represents an n-butyl group, R, in the 6-position may a.Lso represent an amino group substituted. by a phernylsulphonyl, cyclohexylmethylaminocarbonyl, 2-carboxycyclohexyl- methylcarbonyl, 2-tert.butxycarbonyl-cyclohexylinethyl- carbonyl, 2-carboxy-3, 4,5, 6-tetrahydrobenzoyl, N~-methyl- phenylaminocarbonyl or 3-cytclohexylpropyl group; a 117 methylamino groiup substituted by a propylsulphonyl, phenylsuiphonyl, methyiphenylsuiphonyl or chiorophenyl- suiphonyl group; an n-pentylamino group substit,-.ted by a phenylsuiphonyl or methoxyphenylsulphonyl group; an n- propylamino group substituted by a methyiphenylsuiphonyl or iethoxyphenylsulphonyl group; an isopropylamino group substituted by a benzoyl or chiorophenylsuiphonyl group; an N-acetyl-cyclohexylmethylamino, 3 5, 6-tetrahydro- phthalimido, hexahyd,4ohomophthali,mido, N- methanesulphonyl-2-phenylethy) amino, N-chlorophenyl- sulphonyl-benzylamino, piperidino, 4-methyl-piperidino or hexamethyleneimino group, and R3 where Arepresents a carboxy group and R 2 represents an n- butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-l, 2-dihydro-3 ,4-tetramethylene- pyrrolidin-1-yl, 3-carboxy--propionyl or 3-carboxy-2- methyl-propionyl group, and where R 3 represents a carboxy group and R. represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R 1 in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents aA n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methyl-aminocarbony! or cyclohexylaininocarbonyl. group and R 1 in the 6-position may represent a 3,3-dimethyl- glutaric acid imido or 4,4-tetramethylene-glutaric acid imido group, and where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R, in the 6-position may also represent an N-benzenesulphonyl-mrathylamino group, and where R 3 represents a tert.butoxycarbonyl group and R 2 118 represents an n-butyl group, R 1 in the 6-position may also represent a 2-carboxycyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; R 2 represents a hydrogen atom or a straight-chained or branched Ci.-alkyl group in which a methylene group may optionally be replaced by a sulphur atom; R 3 represents a carboxy, cyano, 1H-tetrazolyl or 1- triphenylmethyl-tetrazolyl group or a (C 1 4 alkcxy)- carbonyl group; and R 4 represents a hydrogen, fluorine, chlorine or bromine atom); and isomers and salts thereof. 2. A compound of formula I as claimed in claim 1 wherein R 1 represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, or by a methyl, methoxy or trifluoromethyl group, and in which the NH- group of the above-menti.oned imidazole rings may additionally be substituted by a C 1 6 -alkyl group cr by a C 3 6 -cycloalkyl group; a benzoxazol-2-yl group optionally substituted by a methyl group; an amino group substituted by a bicyclohexylcarbonyl, biphenylcarbonyl or benzofuryl-2-carbonyl group; an aminocarbonylamino group substituted in the 3-pc3ition by a bicyclohexyl or biphenyl group; a 6- or 7-membered alkyleneimino or alkenyleneimino group optionally substituted by one or two methyl groups or by a tetramethylene or pentamethylene group wherein a methylene group is replaced by a carbonyl or sulph,vyl group; a 3,4,5,6- 119 tetrahydro-2 (1H) -pyrimirlinone jroup optionally substituted by a methy. or benzyl group; a hydroxy(C 4 alkyl)aminocaroonyl group, a maleic acid ainido or maleic acid imido group optionally substituted by one or two substituents which may be the sa'ae or different selected from methyl and phenyl groups; an imidazolin-2-yl or iMidaZol-2-yl group substituted in the 1-position by a C 1 6 alkyl group or b- a C 3 -cycloalkyl group; an imidazolidinedione group optionally substituted by, a methyl, benzyl, tetramethylene or pentamethylene group; a methylamino or benzylamino group substituted by a butanesulphonyl group or by a phenylmethanesulphonyl group; an amino or methylamino group substituted by a naphthal1enesulpho nyl group in which the naphthalene ring may be substituted by a dimethylamino group or by 2 methoxy groups, a pyridazin-3-one or dihydro-pyridazin- 3-one gr(,p optionally substituted. by a methyl or benzyl group; a pyrrolidino, piperidino or hexameth"Jleneimino group substituted by two methyl groups; a heptamethyleneimino, 18, 3H-guin-azolin-2, 4-dion-3-yl, hydroxycyclohexylamin -carbonyl, 4, oxazolin-2-yl, 7-nitro-benzofurazan-4-yl-amino or 7- nitro-br'nzofurazan-4-yl-aminopropionylamino group, and wThere k 3 represen-t-s a carboxy group and R 2 represents an 2 n-butyl group, R 1 in the 6-position may also represent an ar.1no group substituted by a phenylsulphonyl, cyclohexylmethyiamiziocarbonyl, 2 -carboxycyclohexj i metftylcarbonyl, 2-tert. -butoxycarboniyl-cyclohexyl- methylcarbonyl, 2-carboxy-3,4, 5, 6-tetrahydrobenzoyl, N- methyl-phenylamtinocarbonyl cr 3-cvclohexylpropyl group; a methylamino, 'roup substituted by a propylsuiphoryl, phenylsulohonyl, 4-methyiphenylsuiphonyl or 4- chlorophenylsulphonyl group; an n-pentylamlno group substituted by a phenylF,'Ilphonyl or 4-methoxyphenyl- sulphonyl group; an n-propylamino group substituted by a 4-methylphenylsulphonyl or 4-methoxyphenylsulphonyl 120 group; an isopropylamino. group substituted by a benzoyl or 4 -chl orophenyl sul phonylI group; an N-acetyl- cyclohexylmethylamino, 3,4,5, 6-tetrahyerophthalimido, hexahylro'nomoplithalimido, N-methanesul phonyl1-2 phenylethylamino, N-(4-chlorophenylsulphonyl) benzylamino, piperidino, 4-methyl -piperidino or n-w~xamethyleneimino group, and where represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-l, 2-dihiydro-3 ,4-tetramethylene- pyrrolidin-l-yl, 3-carboxy-propionyl or 3-carboxy-2- methyl-propionyl group, and where R 3 represents a carboxy group and R 2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R, in the 6-position may also represent a pyrrolidino-carbionylamino group, and 0 G where R 3 represents a tetrazolyl group and R 2 represents G 9 :an n-butyl group, Ri in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylaminocarbonyl or cvclohexylaminocarbonyl group and Rin the 6-position may also represent a 3,3-dimethyl- so gtriacdiioo44-tetraniethylene-glutaric acid. '*Goesimido group, and 9 where R. represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R 1 in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and where R 3 represents a tert.butoxycarbonyl group anid Pz represents an n-butyl group, R 1 in the 6-positi-on may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group; R 2 represents a hydrogen atom or a straight-chained or A, ;I*
121. branched Cl-4-a ikyl group in which a methylene group may be replaced by a sulphur atom; R 3 represents a carboxy, cyano, lH-tetrdizolyl or 1- triphenylmethyl -tetra zolyl group or a (C 1 4 alkoxy) carbonyl group; and R 4 represents a hydrogen, fluorine, chlorine or bromine atom; and the 3-isomer mix-cures and salts thereof with organic or inorganic acids or bases. 3. A compound of formula I as claimed in claim 1 or claim 2 wherein R 1 in the 6-position represents a l-methylbenzimidazol-2- yl, 3,4,5, 6-tetrahydro-phthalimino, 2, 3-diphenyl-maleic ;icid imido, 2,3-dimethyl-maleic acid imido, N-phenyl- a methanesulphonyl- inethy.aiino, 2-oxo-pyrrolidin-1-yl, 2- oxo-piperidin---yl, 2-oxo-hexamethyleneimino, 2-oxo-3 ,4- tetramethylene-pyrrolidin-l-yl, 3, 3-dimethylgluzarimido, V, a N-methylarinocarbonyl-n-pentylamino, propanesultam-l -yl or butanesultam-l-yl group; 2 represents a methyl, ethyl, n-propyl or n-butyl group; R 3 reoresents a carboxy or'lH-tetrazolyl group; and R 4 represents a hydrogen atom; and the salts thereof with organic or inorganic acids or bases. 4. A compound as claimed in any one of claims 1 to 3 being e, 122 4 [2-n-propyl-6-(l-nethylbenzirnidazol-2-yl) benzimidazol-1-ytl]methyljbiphenyl-2-carboxylic acid; 4'-[[2-n-butyl-6-(3,4,5,6-tetrahydro-phthalimino)- benzimidazol-1-yllmethyl]biphenyl-2-carboxylic acid; [2-n-butyl-6-(2,3-diphenyl-naleic acid imido) benzimidazol-1-y1]methyl]biphenyl-2-carboxyic~ acid; 4 [2-n-butyl-6-(2,3-dinethyl-naleic acid imido)- benzimidazol-1-yl]xnethyl~biphenyl-2-carboxylic acid; [[2-n-butyl-6- (N-phenylmethanesulphoiyl-methylanino) benzimidazol-1-yl]methyl]biphenyl-2-carboxylic acid; 4 '-n-butyl-6- (2-oxo-piperidin-1-yl) -benzimidazol-l- yljmethyl]-2- (1H-tetrazol-5-yl) -biphenyl; 4 [2-n-butyl-E-(2-ox-peylgdin-1-yl) -benzimidazol- yl]methyl] (H-tetrazol-5-yl) -bipheny; [2-n-butyl-6-(2-oxoheamethylebniino)-etlmn) benzimidazol-1-yl liethyl] (1H-tetrazol-5-y1) -biphenyl; 4 [[2-n--butyl-6- 3-dietylglutoarbndo)-nzidzl n)beziiaz1-yl]methyl]-2- (1Htetazo-5-y) -iphnyl [[2-n-butyl-6- (N-inethylaminocarboyl-n-pntyliin) benzimziidzol--l1-yl]-2- (1bihtetral--yl)oxi -bphnld; L0 00. 0 fe 000*0* 0. 0 123 4' [2-n-butyl-6- (propanesultama-l-yl) -benzimidazol-l- yl]methyl]-2-(lH-tetrazol-,3-yl) -biphenyl; 4 [2-n-propyl-6-(butanesultamn--yl) -benzimidazol-l- yl] methyl] (lH-tetrazol-5-yl) -biphenyl; 4 [2-n-butyl-6-(butanesultam-l-yl) -benzimidazol-l- yl~methyl]-2- (lH-tetrazol-5-yl) -biphenyl; 4 '-[[2-n-propyl-6-(l-methyl-benzimidazol-2-yl)- benzimidazol-1-yllimethyl] (lH-tetrazol-5-yl) -biphenyl; or 4 [2-n-propyl,-6-(2-oxo-piperidin-l-yl)-benzimidazol-l- yljmethyl] (lH-tetrazol-5-yl) -biphenyl; or a salt thereof with an organic or inorganic acid or base. A compound as claimed in any one of claims 1 to 4 being a physiologically acceptable salt of a compound of formula I. 6. A process for the prepartion of compounds as claimed in claim 1, said process comprising at least one of the following steps: a) cyclising a compound of formula II 555555 S 5050 a a .5 a S OS. *S 05 S S. S. S 05 I I) (wherein Ris as defined in. any one of clains 1 to 4; 124 one of the groups X, or Y 1 represents a group of formula R 3 \R4 N/ R and the other group X 1 or Y1 represents a group of formula NH C R2 R 2 R 3 and R 4 are as defined in any one of claims 1 to 4, Rg represents a hydrogen atom or an R 2 CO group; Z i and Z 2 which may be the same or different, represent optionally substituted amino groups or hydroxy or mercapto groups optionally substituted by lower alkyl groups, or Z and Z 2 together represent an oxygen or sulphur atom, an imino group optionally substituted by a C. 3 -alkyl group, or a Cz 2 -alkylenedioxy or C 2 3 alkylenedithio group, with the proviso that one of the groups X 1 or Y, must represent a group of formula 9 3 0 R4 NCOR 125 or zi Z2 NH C R 2 or an N-oxide thereof and optionally subsequently reducing a cyclized N-oxide thus obtained; b) reacting a benzimidazole of formula III RR 2 JL (ill) H (wherein RI and R2 are as defined in any one of claims 1 to 4), with a biphenyl compound of formula IV 9 *R (IV) Z 3 (wherein R 3 and R4 are as defined in any one of claims 1 to 4; and Z 3 represents a nucleophilic leaving group); c) (to prepare a compound of formula I wherein R 3 represents a carboxy group) converting a compound of formula V so* 0 converting a compound of formula V 126 "wherein R 2 and R 4 are as defined in any one of claims 1 to 4; R i is a group R i as defined in any one of claims 1 to 4 or a 3-((Cl. 3 alkoxy)carbonyl)propionyl or 3-((C 1 3 alkoxy)carbonyl)-2-methylpropionyl group; and R 3 represents a group which may be converted into a carboxy group by hydrolysis, thermolysis or hydrogenolysis) into a corresponding carboxy compound; or d) (to prepare a compound of formula I wherein R 3 represents a 1H-tetrazolyl group) cleaving a protecting group from a compound of formula VI R 2 R *N RR (wherein R, R 2 and R4 are as defined in any one of claims 1 to 4; and R 3 represents a 1H-tetrazolyl group protected in the 1- or 3-position by a protecting group); e) (to prepare a compound of formula I wherein R 3 represents a 1H-tetrazolyl group) reacting a compound of S: formula VII R RX^ 2 I)(viI) N u 127 (wherein RI, R 2 and R 4 are as defined in any one of claims 1 to 4) with hydrezoic acid or a salt thereof; f) (to prepare compounds of formula I wherein R i represents a pentamethylene-oxazolin-2-yl group) reacting a compound of formula VIII HOOC R2 (VI I) R, (wherein R 2 R 3 and R4 are as defined in any one of claims 1 to 4) with 1-aminomethyl-cyclohexanol in the presence of an acid-activating agent; g) (to prepare a compound of formula I wherein R i represents a 2-oxo-3,4-tetramethylene-pyrrolidin-l-yl group) hydrogenating a compound of formula IX **S e00X N 2 (Ix) CH R (wherein R 2 R 3 and R4 are as defined in any one of claims 1 to 4); h) (to prepare compounds of formula I wherein R 1 represents an amino group substituted by a 128 bicyclohexylcarbonyl. or biphenylcarbonyl group, which may additionally be substituted at the N-atom by a C 1 3 alkyl group, an aminocarbonylamino group substituted by a bicyclohexyl or biphenyl group and optionally additionally substituted by one or two C 1 alkyl groups at the N-atom, a maleic. acid amido or maleic acid imido group optionally mono- or disubstituted by substituents selected from C 1 3 -alkyl and phenyl. groups, a C 1..3 alkylamino or phenyl. (Cl.. 3 alkyl) amino substituted by a C- alkylsuiphonyl group or by a phenyl(C 1 3 -alkyl)sulphonyl group, an amino or C 1 3 alkylamino group substituted by a naphthalenesulphonyl. group and optionally substituted in the naphthalene ring by a di(C 1 3 alkyl)amino group or by one or two C 1- 3 -akoxy groups, a 7-nitro-benzofurazan-4- .yl-amino(C 2 3 alkanoyl) amino group, a benzofurancarbonyl- amino or 7-nitro-benzofurazan-4-yl-amino group, and where R 3 represents a carboxy group and R 2 represents an S6*n-butyl group, R, in the 6-position may also represent an amino group substituted by a phenylsuiphonyl, cyclohexylmethylaminocarbonyl, 2 -carboxycycl o- hexylmethylcarbonyl, 2-tert. -butoxycarbonyl- cyclohexylmethylcarbonyl, 2-carboxy-3,4,5,6- tetrahydrobenzoyl, N-methyl-phenylaminocarbonyl or 3- cyclohexyipropyl group, a methylamino group substituted V. by a propylsulphonyl, phenylsulphonyl, methylphenylsulphonyl or chlorophenylsulphonyl group, an n-pentylamino group substituted by a phenylsulphonyl or methoxyphenylsulphonyl. group, an n-propylamino group 6: substituted by a methylphenylsulphonyl or methoxyphenyl- sulphoryl group, an isopropylamino group substituted by a benzoyl. or chlorophenylsulphonyl group, an N.-acetyl- cyclohexylmethylami4no, 3,4,5, 6-tetrahydrophthalimido, hexahydrohomophthalimido, N-methanesulphonyl-2- phenyl ethyl amino or N-chl orophenyl sulphonyl -benzylamino group, and 129 where R 3 represents a carboxy group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent a 2-oxo-l,2-dihydro-3,4-tetramethylene- pyrrolidin-1-yl group, and where R 3 represents a carboxy group and R 2 represents a methyl, ethyl, n-propyl, n-butyl or methylmercapto group, R, in the 6-position may also represent a pyrrolidino-carbonylamino group, and where R 3 represents a tetrazolyl group and R 2 represents an n-butyl group, R 1 in the 5- or 6-position may also represent an n-pentylamino group substituted by a methylamino-carbonyl or cyclohexylaminocarbonyl group and R 1 in the 6-position may also represent a 3,3- S: dimethyl-glutaric acid imido or 4,4-tetramethylene- glutaric acid imido group, and where R 3 represents a tetrazolyl group and R 2 represents an ethyl or n-propyl group, R I in the 6-position may also represent an N-benzenesulphonyl-methylamino group, and °where R 3 represents a tert.-butoxycarbonyl group and R 2 represents an n-butyl group, R 1 in the 6-position may also represent a 2-carboxy-cyclohexylmethylcarbonylamino or pyrrolidinocarbonylamino group) reacting a compound of formula X *6 B N_\ (wherein Li 130 R 2 R 3 and R4are a5 defined in any one of claims 1 to 4; and R 6 represents a hydrogen a±tom, an n-pentyl, cyclohexyl- methyl, Cl- 3 -alkyl or phenyl(Cl. 3 alkyl) group) with a compound of formula XI z- W R7(XI) (wherein Z 4 represents a nucleophilic leaving group;- W represents a -Ca- or group; and 7 represents a 2-hydroxycarbonyl-ethenyl group wherein the ethenyl moiety is mono- or disubstituted by, selected from C 1 3 -aikyl and phenyl groups, a C 3 6 -alkyl group, a phenyl(c 1 3 alkyl) group, a naphthalene group optionally substituted by a d(l3 Salkyl)amino group or by one or two C 1 3 alkoxy groups, a methyl, phenyl, methylphenyl, methoxyphenyl, 'a,'chlorophenyl, biphenyl, bicyclohexyl, 2-carboxy- cyclohexylmethyl, 2-carboxy-3 6-tetrahydrophenyl, 3- carboxy-l, 1-dimethyl-propyl, 3-carboxy-2 ,2- tetramethylene-propyl, 7-nitro-benzofurazan-4-yl- a:...:aminomethyl or 7-nitro-benzofurazan-4-yl-aminoethyl group, and whrr Wrepresents a-CO- grup R ma also rerseta R 8 NR 9 group wherein R 8 represents a hydrogen atom or a C 1 l 3 -alkyl group, 5 R 9 represents a methyl, cyclohexyl, cyclohexylmethyl, phenyl, biphenyl or bicyclohexyl group, or R. and R 9 together with the nitrogen atom between them represent a pyrrolidino group, or 131 Z 4 together with R 9 represents another carbon- nitrogen bond, and R 7 together with W may also r present a 7-nitro- benzofurazan-4-yl-amino group) or with a reactive derivative of a carboxylic acid of formula XI; i) (to prepare compounds of formula I wherein R i represents a tetrahydrobenzimidazolyl or imidazopyridinyl group, a benzimidazolyl group optionally substituted in the phenyl nucleus by a fluorine, chlorine or bromine atom, by a C.. 3 -alkyl group, by a C 1 ,-alkoxy group or by a trifluoromethyl group, and in which the NH-group of the above-mentioned *S* imidazole rings may additionally be substituted by a SC 1 6 -alkyl group or by a C 3 7 -cycloalkyl group, a hydroxy(C. 7 -cycloalkyl)aminocarbonyl group, which may additionally be substituted at the N-atom by a C 1 3 -alkyl group, or a straight-chained or branched hydroxy(C 4 6 alkyl)aminocarbonyl group) reacting a compound of formula XII R 4 (wherein R 2 R 3 and R4 are as defined in any one of claims 1 to 4) or a reactive derivative thereof with an amine of formula XIII R 1 0 Ri N H (XIII) R 11 132 (wherein R 1 represents a hydrogen atom, a cycloalkyl group or a C 1 6 -alkyl group; and R 11 represents a C 4 6 -hydroxyalkyl group, a C 5 7 ,-hydroxy- cycloalkyl group or a 2-aminophenyl group which may be s'2:stituted in the phenyl nucleus by a fluorine, chl,orine or bromine atom, by a C,.,-alkyl group, by a C 1 alkoxy group or by a trifluoromethyl group, a 2- aminocyclohexyl or 2-aminopyridyl group) optionally with simultaneous decarboxylation; j) (to prepare compounds of formula I wherein R, represents a dihydro-pyridazin-3-one or pyridazin-3-one group which may be substituted in the 2-position by an as optionally piIenyl-substituted C 1 3 -alkyl group or at a carbon atom by one or two C 1 3 -alkyl groups) reacting a carboxylic acid of formula XIV HOCAC( V *BieR, to**: S (wherein a. P9,.2 3adRar sdfndi nyoeo lis1t Sao~-C -j F 4 4; and) A reresntsan thylne r ehenlenegrop otioall substituted~ bonortoC alygrous o (wheare in A 1 represents a ehylroena or thnln u optionally nl ~substituted by one ol r oup 1 3 aklgop)o 133 k) resolving a 3-isomer mixture of a compound of formula I thus obtained by isomer separation into the 1- and !-isomers thereof; 1) converting a compound of formula I thus obtained into a salt thereof or a salt of a compound of formula I into the free compound; and m) carrying out a reaction according to any one of said steps tr in which one or more groups are protected by a protecting group and subsequently removing any protecting group used. 7. A pharmaceutical composition comprising a compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable salt thereof together with at least one pharmaceutical carrier or excipient. 8. A method of treatment of the human or non-human animal body to combat hypertension, cardiac insufficiency, ischaemic peripheral circulatory disorders, myocardial ischaemia (angina), cardiac insufficiency progression following myocardial infarction, diabetic nephropathy, glaucoma, gastrointestinal diseases and bladder diseases said method comprising administering to said body a compound of formula I as claimed in any one of claims 1 to 4 or a physiologically acceptable salt thereof. 9 9. A compound of formula I is claimed in claim 1 or a pharmaceutical composition thereof substantially as herein disclosed in any one of the Examples. DATED this 9th day of June 1993. DR KARL THOMAE GMBH SA 4, By their Patent Attorneys: tv, o \LINAN WRIE, \p C,1 t *l l Wiv o t~ y JKaJ.^ jAAV VAR< Abstract. The invention relates to benzimidazoles of formula I N R 3 I -R4 (wherein R 1 RV, R 3 and R 4 are as defined in claim 1) and the 1-, 3-isomer mixtures and the salts thereof, compoirnds which BB B have valuable properties, in particular as -,ngiotensin- II antagonists. 0 a so
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4023369 | 1990-07-23 | ||
| DE4023369A DE4023369A1 (en) | 1990-07-23 | 1990-07-23 | New 1-bi:phenylyl:methyl benzimidazole derivs. |
| DE4031287 | 1990-10-04 | ||
| DE4031287A DE4031287A1 (en) | 1990-07-23 | 1990-10-04 | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| DE4105324 | 1991-02-20 | ||
| DE4105324A DE4105324A1 (en) | 1990-07-23 | 1991-02-20 | BENZIMIDAZOLE, MEDICAMENTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AU8122791A AU8122791A (en) | 1992-01-30 |
| AU640505B2 true AU640505B2 (en) | 1993-08-26 |
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ID=27201487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU81227/91A Expired AU640505B2 (en) | 1990-07-23 | 1991-07-23 | Benzimidazoles |
Country Status (18)
| Country | Link |
|---|---|
| EP (1) | EP0468470B1 (en) |
| JP (1) | JP2539113B2 (en) |
| AT (1) | ATE151766T1 (en) |
| AU (1) | AU640505B2 (en) |
| CA (1) | CA2047496C (en) |
| CS (1) | CS230491A3 (en) |
| DE (1) | DE59108658D1 (en) |
| DK (1) | DK0468470T3 (en) |
| ES (1) | ES2100907T3 (en) |
| FI (1) | FI105811B (en) |
| GR (1) | GR3024027T3 (en) |
| HU (1) | HUT58298A (en) |
| IE (1) | IE912563A1 (en) |
| IL (1) | IL98933A (en) |
| NO (1) | NO178927C (en) |
| NZ (1) | NZ239089A (en) |
| PT (1) | PT98414B (en) |
| RU (1) | RU1836357C (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU660209B2 (en) * | 1992-01-22 | 1995-06-15 | Dr. Karl Thomae Gmbh | Heteroaryl substituted biphenylmethyl benzimidazoles |
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| GB8904174D0 (en) * | 1989-02-23 | 1989-04-05 | British Bio Technology | Compounds |
| NZ232785A (en) * | 1989-03-15 | 1991-03-26 | Janssen Pharmaceutica Nv | 5-(1,2 benzisoxazol-, benzimidazol and benzisothiazol-3- yl)-1h-benzimadazol-2-yl carbamic acid ester derivatives preparatory processes, intermediates and anthelmintic compositions |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| SI9210098B (en) * | 1991-02-06 | 2000-06-30 | Dr. Karl Thomae | Benzimidazoles, drugs with this compounds, and process for their preparation |
| US5591762A (en) * | 1991-02-06 | 1997-01-07 | Dr. Karl Thomae Gmbh | Benzimidazoles useful as angiotensin-11 antagonists |
| US5602127A (en) * | 1991-02-06 | 1997-02-11 | Karl Thomae Gmbh | (Alkanesultam-1-yl)-benzimidazol-1-yl)-1yl)-methyl-biphenyls useful as angiotensin-II antagonists |
| US5594003A (en) * | 1991-02-06 | 1997-01-14 | Dr. Karl Thomae Gmbh | Tetrahydroimidazo[1,2-a]pyridin-2-yl-(benzimidazol-1-yl)-methyl-biphenyls useful as angiotensin-II antagonists |
| DE4224133A1 (en) * | 1992-07-22 | 1994-01-27 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| DE4224752A1 (en) * | 1992-04-11 | 1994-02-03 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| US5798364A (en) * | 1992-03-26 | 1998-08-25 | Merck Patent Gesellschaft Mit Beschrankter Haftung | Imidazopyridines |
| IL103020A (en) * | 1991-09-10 | 1998-10-30 | Tanabe Seiyaku Co | 3-(1,1'-Biphenyl-4-yl-methyl)-4,5,6,7-tetrahydro-3h-imidazo Ú4,5-c¾ pyridine-4-carboxylic acids their preparation and pharmaceutical compositions containing them |
| EP0543263A3 (en) * | 1991-11-16 | 1993-08-25 | Dr. Karl Thomae Gmbh | Benziimidazoles, pharmaceuticals containing them and process for their preparation |
| DE4219534A1 (en) * | 1992-02-19 | 1993-12-16 | Thomae Gmbh Dr K | Substituted biphenylyl derivatives, pharmaceutical compositions containing them and methods for their preparation |
| DE4207904A1 (en) * | 1992-03-12 | 1993-09-16 | Thomae Gmbh Dr K | SUBSTITUTED BENZIMIDAZOLYL DERIVATIVES, MEDICAMENTS CONTAINING SUCH COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF |
| US5612360A (en) * | 1992-06-03 | 1997-03-18 | Eli Lilly And Company | Angiotensin II antagonists |
| DE4237656A1 (en) * | 1992-06-13 | 1993-12-16 | Merck Patent Gmbh | benzimidazole derivatives |
| GB9218449D0 (en) | 1992-08-29 | 1992-10-14 | Boots Co Plc | Therapeutic agents |
| DE4304455A1 (en) * | 1993-02-15 | 1994-08-18 | Bayer Ag | Heterocyclic substituted phenyl-cyclohexane-carboxylic acid derivatives |
| DE4408497A1 (en) * | 1994-03-14 | 1995-09-21 | Thomae Gmbh Dr K | Benzimidazoles, medicaments containing these compounds and process for their preparation |
| US5753672A (en) * | 1994-04-19 | 1998-05-19 | Tanabe Seiyaku Co., Ltd. | Imidazopyridine derivatives and process for preparing the same |
| NZ290008A (en) * | 1994-06-29 | 1998-08-26 | Smithkline Beecham Corp | Vitronectin receptor antagonists, comprising a fibrinogen antagonist analogue linked to a heterocycle |
| WO1997024334A1 (en) * | 1995-12-28 | 1997-07-10 | Fujisawa Pharmaceutical Co., Ltd. | Benzimidazole derivatives |
| TW453999B (en) | 1997-06-27 | 2001-09-11 | Fujisawa Pharmaceutical Co | Benzimidazole derivatives |
| SE9903028D0 (en) | 1999-08-27 | 1999-08-27 | Astra Ab | New use |
| DE10314702A1 (en) * | 2003-03-31 | 2004-10-21 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Process for the preparation of telmisartan |
| US7098342B2 (en) * | 2003-10-16 | 2006-08-29 | Teva Pharmaceutical Industries Ltd. | Preparation of candesartan cilexetil |
| MX2007004426A (en) * | 2004-10-15 | 2007-06-14 | Teva Pharma | Process for preparing telmisartan. |
| MX354786B (en) | 2007-06-04 | 2018-03-21 | Synergy Pharmaceuticals Inc | AGONISTS OF GUANYLATE CYCLASE USEFUL FOR THE TREATMENT OF GASTROINTESTINAL DISORDERS, INFLAMMATION, CANCER and OTHER DISORDERS. |
| US8969514B2 (en) | 2007-06-04 | 2015-03-03 | Synergy Pharmaceuticals, Inc. | Agonists of guanylate cyclase useful for the treatment of hypercholesterolemia, atherosclerosis, coronary heart disease, gallstone, obesity and other cardiovascular diseases |
| ES2522968T3 (en) | 2008-06-04 | 2014-11-19 | Synergy Pharmaceuticals Inc. | Guanylate cyclase agonists useful for the treatment of gastrointestinal disorders, inflammation, cancer and other disorders |
| AU2009270833B2 (en) | 2008-07-16 | 2015-02-19 | Bausch Health Ireland Limited | Agonists of guanylate cyclase useful for the treatment of gastrointestinal, inflammation, cancer and other disorders |
| MX2011012537A (en) | 2009-05-29 | 2011-12-14 | Sumitomo Chemical Co | Agent for treatment or prevention of diseases associated with activity of neurotrophic factors. |
| US9616097B2 (en) | 2010-09-15 | 2017-04-11 | Synergy Pharmaceuticals, Inc. | Formulations of guanylate cyclase C agonists and methods of use |
| AU2014235215A1 (en) | 2013-03-15 | 2015-10-01 | Synergy Pharmaceuticals Inc. | Agonists of guanylate cyclase and their uses |
| AU2014235209B2 (en) | 2013-03-15 | 2018-06-14 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists combined with other drugs |
| BR112015030326A2 (en) | 2013-06-05 | 2017-08-29 | Synergy Pharmaceuticals Inc | ULTRAPURE GUANYLATE CYCLASE C AGONISTS, METHOD OF MANUFACTURING AND USING THEM |
| JP6461118B2 (en) | 2013-06-21 | 2019-01-30 | ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． | Novel substituted bicyclic compounds as bromodomain inhibitors |
| SI3010503T1 (en) * | 2013-06-21 | 2020-07-31 | Zenith Epigenetics Ltd. | Novel bicyclic bromodomain inhibitors |
| JP6542212B2 (en) | 2013-07-31 | 2019-07-10 | ゼニス・エピジェネティクス・リミテッドＺｅｎｉｔｈ Ｅｐｉｇｅｎｅｔｉｃｓ Ｌｔｄ． | Novel quinazolinones as bromodomain inhibitors |
| JP2017523214A (en) * | 2014-08-05 | 2017-08-17 | ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ | Heterocyclic kinase inhibitor |
| US10710992B2 (en) | 2014-12-01 | 2020-07-14 | Zenith Epigenetics Ltd. | Substituted pyridinones as bromodomain inhibitors |
| WO2016092375A1 (en) | 2014-12-11 | 2016-06-16 | Zenith Epigenetics Corp. | Substituted heterocycles as bromodomain inhibitors |
| CA2966450A1 (en) | 2014-12-17 | 2016-06-23 | Olesya KHARENKO | Inhibitors of bromodomains |
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| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| AU6461290A (en) * | 1989-10-24 | 1991-05-02 | Takeda Chemical Industries Ltd. | Benzimidazole derivatives, their production and use |
| AU629324B2 (en) * | 1989-04-08 | 1992-10-01 | Dr. Karl Thomae Gmbh | Benzimidazoles |
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| US4820843A (en) * | 1987-05-22 | 1989-04-11 | E. I. Du Pont De Nemours And Company | Tetrazole intermediates to antihypertensive compounds |
| EP0400835A1 (en) * | 1989-05-15 | 1990-12-05 | Merck & Co. Inc. | Substituted benzimidazoles as angiotensin II antagonists |
| JP2568315B2 (en) * | 1989-06-30 | 1997-01-08 | イー・アイ・デュポン・ドゥ・ヌムール・アンド・カンパニー | Fused ring aryl substituted imidazole |
| IE70593B1 (en) * | 1989-09-29 | 1996-12-11 | Eisai Co Ltd | Biphenylmethane derivative the use of it and pharmacological compositions containing same |
| IL96019A0 (en) * | 1989-10-31 | 1991-07-18 | Fujisawa Pharmaceutical Co | Imidazole derivatives,processes for the preparation thereof and pharmaceutical compositions containing the same |
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1991
- 1991-07-04 RU SU915001010A patent/RU1836357C/en active
- 1991-07-22 JP JP3181033A patent/JP2539113B2/en not_active Expired - Lifetime
- 1991-07-22 DK DK91112404.8T patent/DK0468470T3/en active
- 1991-07-22 EP EP91112404A patent/EP0468470B1/en not_active Expired - Lifetime
- 1991-07-22 FI FI913503A patent/FI105811B/en not_active IP Right Cessation
- 1991-07-22 PT PT98414A patent/PT98414B/en not_active IP Right Cessation
- 1991-07-22 NO NO912859A patent/NO178927C/en not_active IP Right Cessation
- 1991-07-22 ES ES91112404T patent/ES2100907T3/en not_active Expired - Lifetime
- 1991-07-22 CA CA002047496A patent/CA2047496C/en not_active Expired - Lifetime
- 1991-07-22 DE DE59108658T patent/DE59108658D1/en not_active Expired - Lifetime
- 1991-07-22 AT AT91112404T patent/ATE151766T1/en not_active IP Right Cessation
- 1991-07-22 IE IE256391A patent/IE912563A1/en not_active IP Right Cessation
- 1991-07-22 HU HU912456A patent/HUT58298A/en unknown
- 1991-07-23 NZ NZ23908991A patent/NZ239089A/en not_active IP Right Cessation
- 1991-07-23 CS CS912304A patent/CS230491A3/en unknown
- 1991-07-23 IL IL9893391A patent/IL98933A/en not_active IP Right Cessation
- 1991-07-23 AU AU81227/91A patent/AU640505B2/en not_active Expired
-
1997
- 1997-07-09 GR GR970401682T patent/GR3024027T3/en unknown
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880804A (en) * | 1988-01-07 | 1989-11-14 | E. I. Du Pont De Nemours And Company | Angiotensin II receptor blocking benzimidazoles |
| AU629324B2 (en) * | 1989-04-08 | 1992-10-01 | Dr. Karl Thomae Gmbh | Benzimidazoles |
| AU6461290A (en) * | 1989-10-24 | 1991-05-02 | Takeda Chemical Industries Ltd. | Benzimidazole derivatives, their production and use |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU660209B2 (en) * | 1992-01-22 | 1995-06-15 | Dr. Karl Thomae Gmbh | Heteroaryl substituted biphenylmethyl benzimidazoles |
Also Published As
| Publication number | Publication date |
|---|---|
| FI105811B (en) | 2000-10-13 |
| ES2100907T3 (en) | 1997-07-01 |
| NO178927B (en) | 1996-03-25 |
| GR3024027T3 (en) | 1997-10-31 |
| DE59108658D1 (en) | 1997-05-22 |
| DK0468470T3 (en) | 1997-09-22 |
| EP0468470A1 (en) | 1992-01-29 |
| JPH04253966A (en) | 1992-09-09 |
| HU912456D0 (en) | 1991-12-30 |
| JP2539113B2 (en) | 1996-10-02 |
| CS230491A3 (en) | 1992-02-19 |
| IL98933A0 (en) | 1992-07-15 |
| FI913503A0 (en) | 1991-07-22 |
| NZ239089A (en) | 1994-07-26 |
| NO912859L (en) | 1992-01-24 |
| NO912859D0 (en) | 1991-07-22 |
| RU1836357C (en) | 1993-08-23 |
| NO178927C (en) | 1996-07-03 |
| IE912563A1 (en) | 1992-01-29 |
| FI913503A7 (en) | 1992-01-24 |
| HUT58298A (en) | 1992-02-28 |
| PT98414B (en) | 1999-01-29 |
| EP0468470B1 (en) | 1997-04-16 |
| ATE151766T1 (en) | 1997-05-15 |
| CA2047496A1 (en) | 1992-01-24 |
| IL98933A (en) | 1995-12-31 |
| CA2047496C (en) | 2001-10-23 |
| PT98414A (en) | 1992-05-29 |
| AU8122791A (en) | 1992-01-30 |
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